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Appendix A: CLINICIAN PACKET

To Be Used at the Initial MM Session

Form

A–1    Clinician Report

A–2    Vital Signs and BAC

A–3    Concurrent Medications

A–4    Naltrexone Information Sheet: Clinician Version

A–5    Acamprosate Information Sheet: Clinician Version

A–6    Medication Instructions Summary

A–7    Modified SAFTEE

A–8    SAFTEE Guidelines: Part 1

A–9    SAFTEE Guidelines for Rating Severity of Adverse Events: Part 2

A–10    Menstrual Calendar

A–11    Serious Adverse Event Report

A–12    Serious Adverse Event Followup Report

A–13    Medication Compliance Plan

A–14    Pill Count

A–15    Day 3 Clinician Phone Contact

To Be Used at All MM Followup Sessions

Form

A–2    Vital Signs and BAC

A–3    Concurrent Medications

A–7    Modified SAFTEE

A–8    SAFTEE Guidelines: Part 1

A–9    SAFTEE Guidelines for Rating Severity of Adverse Events: Part 2

A–10    Menstrual Calendar

A–14    Pill Count

To Be Used as Needed

Form

A–11    Serious Adverse Event Report

A–12    Serious Adverse Event Followup Report

A–16    COMBINE Study Fact Sheet for the Practitioner**

** The COMBINE Study Fact Sheet provides background clinical information about COMBINE to practitioners using this manual.

 

Form A–1

Clinician Report

 

patient info

Note: Attached to this form are copies of the patient’s demographic summary, medical history, and source documentation for the sections below.

I. Medical Information

A. The most recent record of your blood pressure was: _____/____ (from Vitals form)

B. Your liver enzymes/bilirubin/uric acid are at the following levels: (from Lab reports)
[Explain the significance of enzyme/bilirubin elevation, if applicable.]

 FemaleMale
AST (SGOT): _____Normal Range_____ iu/l_____ iu/l
ALT (SGPT): _____Normal Range_____ iu/l_____ iu/l
GGT (GGTP): _____Ranges_____ iu/l_____ iu/l
Bilirubin: _____Normal Range_____ mg/dl_____ mg/dl
Uric Acid: _____Normal Range_____ mg/dl_____ mg/dl

C. Other abnormal lab values: (from Lab reports)

a) __________________________
b) __________________________
c) __________________________
d) __________________________

D. You have the following drinking-related medical symptom(s)/condition(s): (from Clin. chart)

a) __________________________
b) __________________________
c) __________________________
d) __________________________

Notes:

II. Alcohol Use

On average, you drink _____ days/week. (From TLFB; Form 90)

On average, you drink _____ drinks per drinking occasion. (From TLFB; Form 90)

Notes:

III. Consequences of Drinking

[Note: From DrInC-L. Discuss one to three items to which the patient responded “yes.” Select the three most clinically relevant items.]

  1.  

  2.  

IV. Diagnostic Information

You have the following symptoms of alcohol dependence: [Check either “Yes” or “No” for each symptom listed below.]

 (from Dx Interview)
YESNO
a) When you start drinking, you end up drinking more, or longer, than you planned.checkboxcheckbox
b) You have tried to, or wanted to, cut down or stop drinking alcohol.checkboxcheckbox
c) You have spent a lot of time drinking or being hung over.checkboxcheckbox
d) You have given up important social, occupational, or recreational activities because of alcohol use.checkboxcheckbox
e) You have continued to drink even though alcohol has caused, or made worse, psychological or physical problems.checkboxcheckbox
f) You have an increased tolerance to alcohol. checkboxcheckbox
g) You have experienced withdrawal symptoms when you cut down or stopped drinking.checkboxcheckbox
h) Your Dx Interview says you meet criteria for alcohol dependence. (At least three symptoms must be checked “YES”)checkboxcheckbox

Notes:

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Form A–2

Vital Signs and BAC

patient info

Instructions: Record the vital signs and BAC at baseline and over the course of treatment.
  1. Blood pressure (sitting): ____________ mmHg Systolic / _____________mmHg Diastolic

  2. Pulse rate: ________________ per minute

  3. Breath alcohol concentration: _______.________

  4. Weight: _______.________ lbs

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Form A–3

Concurrent Medications

patient info

Instructions: At the baseline visit, the time frame used for asking about concurrent medications is the past 90 days because this is consistent with the time frame used for Form 90 and the SAFTEE. Be sure to also ask about the use of acamprosate or naltrexone in the last 30 days. Also inquire about the use of concomitant medications at each subsequent visit (this form is cumulative).
 
Week # / Sequence # Medication Primary Indication Started Prior to Tx?Date StartedOngoing at End of Tx?Date Stopped Notes
YesNo(mm/dd/yy)Yes No(mm/dd/yy)
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  
/   checkboxcheckbox /     / checkboxcheckbox /     /  

If medications are used for an adverse experience, list the event on the SAFTEE.

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Form A–4

Naltrexone Information Sheet: Clinician Version1

(1 Adapted from Rounsaville, B.J.; O’Malley, S.; and O’Connor, P. “Guidelines for the Use of Naltrexone in the Treatment of Alcoholism.” New Haven, CT: APT Foundation, 1995. Reproduced with the permission of DuPont Pharma.)

  1. What is naltrexone, and how does it work?

    Naltrexone is a medication that blocks the effects of drugs known as opiates, or narcotics (a class that includes morphine, heroin, or codeine). It competes with these drugs for opioid receptors in the brain. Originally used to treat dependence on opiate drugs, it now has also been approved by the U.S. Food and Drug Administration (FDA) as treatment for alcohol dependence. People who are dependent on opiate drugs, such as heroin or morphine, must stop their drug use at least 7 days before starting naltrexone. Some people should not take naltrexone, such as those suffering from chronic pain who rely on opioid painkillers or people with liver failure or acute hepatitis. Although the precise mechanism of action for naltrexone’s effect is unknown, reports from successfully treated patients suggest the following three kinds of effects:

    • Naltrexone can reduce the patient’s urge or desire to drink.

    • Naltrexone helps patients remain abstinent.

    • Naltrexone can interfere with the patient’s desire to continue drinking more if he/she slips and has a drink.

    In most clinical trials evaluating the effectiveness of naltrexone, subjects who received naltrexone were significantly more successful in remaining abstinent and in avoiding relapse than were those receiving an inactive placebo pill.

  2. Is it possible to become addicted to naltrexone?
  3. No. Naltrexone is not habit forming or a drug of abuse. It does not cause users to become physically or psychologically dependent.

  4. What are the side effects of naltrexone?

    In a large open-label safety study on naltrexone, conducted by Dupont Pharma in 570 individuals with alcoholism, the most common side effects affected only a small minority of people; they included the following:

    • Nausea (10 percent of participants)

    • Headache (7 percent of participants)

    • Depression (5 to 7 percent of participants)

    • Dizziness (4 percent of participants)

    • Fatigue (4 percent of participants)

    • Insomnia (3 percent of participants)

    • Anxiety (2 percent of participants)

    • Sleepiness (2 percent of participants).

    These side effects were usually mild and of short duration. The side effects, predominantly nausea, have been severe enough to cause 5 to 10 percent of people starting it to stop the medication. Patients usually report that they are largely unaware of being on naltrexone. Naltrexone usually has no psychological effects, and users do not feel either “high” or “down.” Naltrexone can have toxic effects on the liver. A patient receives blood tests of liver function prior to the onset of treatment and regularly during treatment to determine if he/she should take it at all, if he/she should stop taking it, or if he/she experiences the relatively rare side effect of liver toxicity. Patients should report any side effects to their medical clinician.

  5. What will happen if the patient drinks alcohol while taking naltrexone?

    Naltrexone does not reduce the effects of alcohol that impair coordination and judgment. Naltrexone may reduce the feeling of intoxication and the desire to drink more, but it will not cause a severe physical response to drinking.

  6. Is it all right to take other medications with naltrexone?
  7. Patients should carry a card explaining that they are taking naltrexone, and it should instruct medical staff on pain management. Naltrexone does not reduce the effectiveness of local and general anesthesia used with surgery. However, it does block pain relief from opiate medications. Many pain medications that are not opiates are available. Patients having elective surgery should stop taking naltrexone at least 72 hours beforehand. The major active effect of naltrexone is on opiate (narcotic) drugs, which is one class of drugs used primarily to treat pain but is also found in some prescription cough preparations. Naltrexone will block the effect of normal doses of this type of drug. There are many nonnarcotic pain relievers patients can use while on naltrexone. Otherwise, naltrexone is likely to have little impact on other medications patients commonly use, such as antibiotics, nonopioid painkillers (e.g., aspirin, acetaminophen/Tylenol, ibuprofen/Motrin/Advil), and allergy medications. Patients should inform their medical clinician of the medication they are currently taking so that possible interactions can be evaluated. Because the liver breaks down naltrexone, other medications that can affect liver function may affect the dose of naltrexone.

  8. What will happen if a patient becomes pregnant while taking naltrexone?
  9. Patients with the biological potential to have a child should be using an effective method of birth control while taking naltrexone. However, if they miss a menstrual period, they should report this to their medical clinician at once and take a pregnancy test. If a patient becomes pregnant, she will discontinue the medication. The medical clinician should continue to ask about her health throughout her pregnancy and also about the health of her baby after delivery.

  10. Should patients take naltrexone with a meal?
  11. There is no information that taking naltrexone with or without meals makes any difference in effect.

  12. What happens if the patient stops taking naltrexone suddenly?
  13. Naltrexone does not cause physical dependence, and patients can stop taking it at any time without experiencing withdrawal symptoms.

  14. If patients take naltrexone, does it mean that they don’t need other treatment for alcohol dependence?
  15. No. Research studies have shown that naltrexone was most effective when it was combined with treatment from professionals and/or mutual-support groups.

  16. What is the relationship of naltrexone to AA and other mutual-support groups?
  17. There is no contradiction between participating in support groups and taking naltrexone. In fact, one multisite study showed that naltrexone-taking subjects who attended mutual-support groups, such as AA, had better outcomes. It is most likely to be effective for patients whose goal is to stop drinking altogether. If other mutual-support group members caution against taking any medications, patients should refer them to the pamphlet “The AA Member—Medications and Other Drugs,” which explicitly states that AA members should not “play doctor” and advise others on medication provided by legitimate, informed medical practitioners or treatment programs.

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Form A–5

Acamprosate Information Sheet: Clinician Version2

(2 Adapted from Mason, B.J., and Goodman, A.M. Brief Intervention and Medication Compliance Procedures—Therapist’s Manual, 1997. http://www.alcohol-free.com.)

  1. What is acamprosate, and how does it work?
  2. Acamprosate is a new, investigative medication for treatment of alcohol dependence already approved in several European countries and currently being studied in clinical trials in the United States. It is thought to reduce the urge for alcohol by working directly on certain neurotransmitters in the brain (chemicals that transmit information between nerve cells) whose balance has been disturbed because of regular, heavy drinking. Although acamprosate can be used in the United States only with permission of the U.S. Food and Drug Administration, it has been available in Europe since 1989 and has recently been approved for marketing by prescription in more than 12 European countries, including Belgium, France, Germany, Ireland, Italy, the Netherlands, Spain, Switzerland, and the United Kingdom. It is estimated that more than 1 million patients have been treated with acamprosate since it became available.

  3. Is acamprosate addictive?
  4. No. Acamprosate is not habit forming or a drug of abuse. It does not cause users to become physically or psychologically dependent.

  5. What are the side effects of acamprosate?
  6. Like virtually all medications, acamprosate can cause side effects, but these are usually minor and subside as patients continue to take the medication. In European controlled clinical trials, the only types of symptoms that were consistently more common in subjects taking acamprosate than in subjects taking placebo were stomach symptoms. These were usually mild, tended to occur when subjects first started taking the medication, and consisted primarily of loose bowel movements or mild diarrhea. Some subjects also had changes in their sex drive—sometimes this was increased and sometimes decreased, but there was no definite pattern. As with many drugs, sometimes people on acamprosate develop skin rashes or itching. In earlier studies, subjects on acamprosate and those on placebo both experienced equal amounts of this type of symptom. Patients should tell their medical clinician of any side effects.

  7. What will happen if the patient drinks alcohol while taking acamprosate?
  8. Acamprosate does not change the way the body metabolizes alcohol, so acamprosate will not make patients feel sick if they drink (i.e., it does not work like Antabuse). In addition, there is no evidence of an added effect of alcohol if the patient drinks while taking acamprosate.

  9. Is it possible to take other medications with acamprosate?
  10. Because acamprosate is eliminated exclusively by the kidneys, drugs that may be toxic to the kidneys, such as aminoglycoside antibiotics (gentamycin and amikacin), should be avoided. Patients should inform their medical clinician of whatever medication they are currently taking so that possible interactions can be evaluated.

  11. What will happen if a patient becomes pregnant while taking acamprosate?
  12. Patients with the biological potential to have a child should be using an effective method of birth control while taking acamprosate. However, if they miss a menstrual period, they should report this to their medical clinician at once and take a pregnancy test. If a patient becomes pregnant, she will discontinue the medication. The medical clinician should continue to ask about her health throughout her pregnancy and also about the health of her baby after delivery. Even though acamprosate should not be used during pregnancy, animal studies have not shown any ill effects on either the course of pregnancy or on the offspring, nor is there any evidence from animal studies that acamprosate causes birth defects.

  13. Should acamprosate be taken with a meal?
  14. Acamprosate can be taken with food, but food does decrease the amount of medication that the body absorbs. Gastrointestinal symptoms may decrease by taking the medication with food.

  15. Is it all right to crush the pills?
  16. Acamprosate pills should not be crushed because they have an enteric coating. Destroying this coating can lead to a worsening of gastrointestinal side effects.

  17. What happens if patients stop taking acamprosate suddenly?
  18. Acamprosate does not cause physiological withdrawal symptoms when it is stopped.

  19. What happens if patients miss a dose?
  20. If patients miss a dose of acamprosate, they should not take it simultaneously with the next scheduled dose; there should be a minimum of 2 hours between doses. If this is not feasible, they should not take the skipped dose. Instead, they should wait until their next scheduled dose, and take only that dose.

  21. If patients take acamprosate, does it mean that they don’t need other treatment for alcohol dependence?
  22. No. Research has shown that acamprosate was most effective when it was combined with treatment from professionals and/or mutual-support groups.

  23. What is the relationship of acamprosate to AA and other mutual-support groups?
  24. There is no contradiction between participating in support groups and taking acamprosate. It is most likely to be effective for patients whose goal is to stop drinking altogether. If other mutual-support group members caution against taking any medications, patients should refer them to the pamphlet “The AA Member— Medications and Other Drugs,” which explicitly states that AA members should not “play doctor” and advise others on medication provided by legitimate, informed medical practitioners or treatment programs.

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Form A–6

Medication Instructions Summary: General Review of Most Frequently Asked Questions

  1. How often should I take the medications?
  2. Take four pills in the morning, two at midday, and two in the evening.

  3. Can I take medications with meals?
  4. Because one of the medications is best taken on an empty stomach to help with absorption, it is best to take the medications about 1 hour before a meal or 2 hours after a meal. However, if you experience or are concerned about stomach problems, take the medications with meals. Discuss this with the clinician prescribing your medications.

  5. What should I do if I miss a dose? Should I take two doses at once?
  6. No. Do not take a double dose of either medication. Allow at least 2 hours between doses.

  7. If I miss a morning dose, should I take the morning dose or the midday dose at midday?
  8. If you miss the morning pills, take them as soon as you remember. If you remember near the time for the midday dose, take the four morning pills, wait 2 hours, and then take the midday dose. Allow at least 2 hours between doses.

  9. Why are there three extra lines of medication in the blister card for each week?
  10. The blister cards have 10 days worth of medication. This includes doses for 7 days of medication plus a few extras in case you find yourself without medications. For example, if you drop a pill down the sink or are unable to come in for your scheduled session, you may need an extra pill.

  11. What should I do if I lose a dose?
  12. If you lose one or more pills, replace it with medication from the corresponding extra medications. For example, if you needed to replace a lost morning dose, go down the morning columns (the first four columns of pills) on the blister card to find the first line of extra medication (eighth row of pills), and take those pills.

  13. Can I crush, cut, or chew the medications?
  14. No; because one of the pills has a protective coating to reduce stomach problems, it is best to take the pills whole.

  15. What should I do with the blister card?
  16. Return the blister card empty or with unused medications at the next visit. Return it even if you did not take all of the pills that were recommended.

  17. Can I remove the medications from the blister card and take them with me?
  18. It is best to keep the pills in their original packaging until you actually take the dose. Although you will be asked about whether you took your medication at each visit, the blister card is another way to keep track of pill-taking. If you take the pills out of the blister card, you might lose them or may not be able to remember if you took those pills. If you absolutely must take the pills out of the blister card, try to remember which pills you removed as well as if you did actually take that dose.

  19. Does it matter where I store the medications?
  20. Do not store the medications in a car, because high temperatures affect them.

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Form A–7

Modified SAFTEE (version used in COMBINE study)

Form A 7 part a

form A 7 part b

form A 7 part c

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Form A–8

SAFTEE Guidelines: Part 13

(3 From Nassima Ait-Daoud, M.D., and Bankole Johnson, M.D., Ph.D., at the University of Texas, San Antonio Health Science Center.)

The Modified SAFTEE (Form A–7) is designed to collect information on adverse health events that the patient experiences during a specified time period of a clinical trial. Clinicians should use the SAFTEE to report patients’ adverse health events regardless of whether these events are suspected to be drug related. This ensures that clinicians report unanticipated events as well as “known or expected” events. The Modified SAFTEE has three general health questions (part A) that ask if the patient has had any health problems since the last visit, has noticed any changes in appearance, or has stopped doing certain activities because of not feeling well.

Preferred Events Terms

The Modified SAFTEE also has a section on what specific events, or problems, the patient has noticed since the last visit (part B). Form A–7 lists 18 terms, which are on the SAFTEE list of 76 preferred-event terms, below. For consistency, raters are asked to use these terms to record the reported event rather than their own terms or the patient’s words. Alternate terms should be used only when a specific protocol requires it and should be standard across all the sites using the same protocol. For events marked by an asterisk(*), additional specifications are needed.

Alphabetical List of Preferred Terms

Abdominal pain
Accidental injury*
Akathisia
Akinesia
Anxiety/nervousness
Appetite decrease
Appetite increase
Attempted suicide
Blurred vision
Breast pain/swelling
Changes in color (urine)
Chest pain
Concentration difficulty
Confusion
Constipation
Coughing
Cramps
Decreased libido
Dental problems*
Depression
Difficulty falling asleep
Difficulty swallowing
Difficulty urinating
Discharge (nipples)
Dizziness/faintness
Drowsiness
Dry mouth
Dyskinesia* (specify where)
Dystonia* (specify where)
Earache
Early morning awakening
Edema* (specify where)
Eye irritation
Fever
Flatulence
Genital discomfort*
Gum problems*
Hair problems*
Headache*
Hypersalivation
Increased frequency (urination)
Increased libido
Increased thirst
Insomnia
Headache
Intercurrent illness*
Interrupted sleep
Irregular heartbeat
Irritability
Itching (specify where)
Loss of consciousness*
Medical or surgical procedure*
Memory problem
Mouth ulcer
Muscle/bone/joint pain*
Nasal congestion
Nausea
Perceptual problems
Poor hearing
Premenstrual tension
Rapid heartbeat
Rash/skin irritation*
Rigidity (muscle)
Sexual dysfunction
Shortness of breath
Sore throat
Sore tongue*
Stomach/abdominal discomfort
Stool discoloration
Somnolence
Tinnitus
Tiredness/fatigue
Tremor
Vomiting
Weight gain
Weight loss
Wheezing

Examination Procedures

When administering the Modified SAFTEE, ask the patient each question and then allow sufficient time for a response. When the patient responds positively, record necessary information about that event.

For the initial visit, the assessment interval is 90 days prior to the visit; this covers the period on Form 90.

For subsequent visits, ask the patient only about events that he/she experienced since the last visit. Remind the patient of the time interval between each session to focus him/her on the appropriate period.

Completion of the Recording Form

If the patient mentions an event while answering one of the three general health questions in part A and describes it again while responding to the list of symptoms in part B, check the “Prev/Rec” box in part B.

Choose one of the following categories for every event the patient mentions:

  • Date of onset: record the month and day that the event first occurred since the last assessment. For the initial assessment, record any event that occurred 90 days prior to the visit.

  • Duration: record any event in increments of days. Events that last less than 1 day should be recorded as 1 day (e.g., an event that lasts 15 minutes on 1 occasion should be recorded as 1 day; an event that lasts 15 minutes on 3 different days should be recorded as 3 days). The duration should not be greater than the interval between the assessments. For the first assessment, the duration should not be greater than 90 days.

  • Pattern: show whether the event occurred on a continuous (“CO”), intermittent (“IN”), or isolated (“IS”) basis.

  • Severity: assess the intensity of the event by referencing the SAFTEE Guidelines for Rating Severity of Adverse Events (Form A–9), through observation, and/or through the patient’s report of subjective distress. Check “MN” for “Minimal,” “MI” for “Mild,” “MO” for “Moderate,” and “S” for “Severe.”

  • Drug related: assess the relationship of drug to event. This category provides the opportunity to indicate the reasons for suspecting a drug-related effect. If no such effect is suspected, check “N” for “No.” “DR” for “Dose-response” indicates that the intensity of the event is related to the dosage level. Check “TO” for “Timing of onset” if the onset of the event has some regular relationship to drug administration (e.g., it always occurs 1 hour after taking the drug). “K” for “Known drug effect” is another reason for suspecting a drug relationship. Check “O” for “Other” if other reasons are possible.

  • Action taken: show the clinician’s response to a particular event: “N” for “None,” “IS” for “Increased surveillance,” “C” for “Contra active RX,” “SU” for “Suspended RX,” “DC” for “Discontinued RX,” “O” for “Other,” “R” for Dose reduction,” and “I” for “Dose increased.”

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Form A–9

SAFTEE Guidelines for Rating Severity of Adverse Events: Part 24

(4 From Robert Swift, M.D., Ph.D., at Brown University Medical School, Providence, Rhode Island.)

An adverse event is defined as any side effect, complaint, new intercurrent illness, exacerbation of a previous illness, or injury that the patient experiences while involved in treatment. The event, if minimal, mild, moderate, or severe, should be documented on part B of the Modified SAFTEE (Form A–7) and described using standard medical terminology. If serious/life threatening, complete the Serious Adverse Event Report (Form A–11) and provide all required information. In addition, document any hospitalizations, or surgical or diagnostic procedures.

Common Symptom Severity Indicators

Severity:

Minimal

Mild

Moderate

Severe

  1. Nausea

    Minimal   Single occurrence lasting less than 2 hours; no change in eating habits

    Mild   Multiple occurrences or duration of longer than 2 hours; no change in eating habits

    Moderate   Intake significantly less than minimum daily requirement, but able to eat

    Severe   No significant nutritional intake

  2. Vomiting

    Minimal   Stomach contractions, retching, or heartburn without emesis

    Mild   One episode in any 24-hour period

    Moderate   Two to 5 episodes in 24 hours, or 1 episode per day on 5 days or less

    Severe   Six to 10 episodes in 24 hours, or more than 1 episode on more than 5 days

  3. Diarrhea

    Minimal   Loose but not watery stools, without cramping or incontinence

    Mild   Diarrhea without cramping or incontinence, or 2 or fewer episodes per day

    Moderate   Diarrhea with cramping, no incontinence, or 3 or more episodes per day

    Severe   Diarrhea with incontinence and cramping, or 6 or more episodes per day

  4. Abdominal Pain

    Minimal   Single occurrence of abdominal pain that is not distressing and does not limit activities

    Mild   Multiple occurrences of abdominal pain that are not distressing and do not limit activities

    Moderate   Single or multiple occurrences of abdominal pain that cause distress but do not limit activities

    Severe   Abdominal pain or cramping of sufficient severity to limit activities

  5. Change in Appetite

    Minimal   Hunger increased or decreased without change in food intake or weight

    Mild   Hunger increased or decreased with change in food intake and pretreatment weight stable, or less than 5-percent reduction or increase

    Moderate   Hunger increased or decreased; change in food intake and 5- to 10-percent weight loss or gain present without intention to diet or gain weight

    Severe   Hunger increased or decreased; weight loss or gain of more than 10 percent of pretreatment weight without intention to diet or gain weight

  6. Headache

  7. Minimal   Single occurrence of headache that is not distressing and does not limit activities

    Mild   Multiple occurrences of headache that are not distressing and do not limit activities

    Moderate   Single or multiple occurrences of headache that cause distress but do not limit activities

    Severe   Headache with pain of sufficient severity to limit activities

  8. Dizziness

  9. Minimal   Occasional transient subjective dizziness, lasting less than 1 minute per occurrence; no impairment of function and no objective findings

    Mild   Subjective dizziness lasting more than 1 minute; no impairment of function and no objective findings

    Moderate   Dizziness with impairment of function or limitation of activities; nystagmus or increased body sway noted on exam

    Severe   Dizziness with impairment of function, falling, or syncope

  10. Fatigue

  11. Minimal   Subjective fatigue without increased need for rest; able to perform all activities of daily living (ADLs)

    Mild   Subjective fatigue with increased need for rest; able to perform all ADLs

    Moderate   Subjective fatigue with increased need for rest; able to perform ADLs only with effort

    Severe   Unable to perform ADLs; able to meet basic needs only with assistance

  12. Nervousness/Anxiety

  13. Minimal   Occasional nervousness/anxiety that does not cause distress or limit activities

    Mild   Occasional nervousness/anxiety that is distressing but tolerable, but does not limit activities

    Moderate   Occasional or persistent nervousness/anxiety that is distressing but tolerable and limits activities

    Severe   One or more panic attacks or persistent nervousness/anxiety that are intolerable

  14. Insomnia

  15. Minimal   Sleep that is not restful but without change in amount or pattern of sleep

    Mild   More than three occasions of unexplained difficulty falling asleep or of increased nocturnal awakenings, but without change in amount of sleep

    Moderate   More than three occasions of unexplained difficulty falling asleep and nocturnal awakenings with significant reduction in sleep, but without daytime impairment of function

    Severe   More than three occasions of unexplained difficulty falling asleep and nocturnal awakenings with significant reduction in sleep, with daytime impairment of function

  16. Somnolence

  17. Minimal   Occasional subjective tiredness but without change in daily activities

    Mild   Persistent subjective tiredness but without change in daily activities

    Moderate   Persistent subjective tiredness; requiring resting or napping less than 2 hours during the day

    Severe   Persistent tiredness that significantly limits daily activities, requiring napping or resting more than 2 hours daily; falling asleep during work, school, or other activities

  18. Depression

  19. Minimal   Occasional depressed mood that does not cause distress or limit activities

    Mild   Occasional depressed mood that is distressing but tolerable, but does not limit activities

    Moderate   Occasional or persistent depressed mood that is distressing but tolerable and is associated with change in activities

    Severe   Suicidal ideation or persistent depression that is intolerable and is associated with change in activities

  20. Itching

  21. Minimal   Localized itching without need to scratch

    Mild   Localized itching with scratching

    Moderate   Generalized itching that is tolerable, does not interfere with sleep or activities

    Severe   Generalized itching that is intolerable, interferes with sleep and/or activities

  22. Skin Rash

  23. Minimal   Localized erythema or localized macular/papular eruption lasting less than 48 hours and without symptoms

    Mild   Localized erythema or localized macular/papular eruption lasting longer than 48 hours and without symptoms

    Moderate   Erythema or macular/papular eruption with pruritis or other associated symptoms involving more than one site on the body

    Severe   Generalized (most of body affected) symptomatic macular, papular, or urticarial or atypical eruption with or without mucous membrane involvement and with or without exfoliative dermatitis or ulcerating dermatitis

  24. Change in Libido

  25. Minimal   Occasional increase or decrease in libido that does not engender distress or concern; no change in sexual activity or performance

    Mild   More persistent libido increase or decrease that does not engender distress or concern; no changes in sexual activity or performance

    Moderate   More persistent libido increase or decrease that does engender distress or concern; change in sexual activity or performance reported

    Severe   Significant increase or total lack of interest in sex that is distressing or of concern; associated with changes in sexual activity or performance

  26. Missed Menses

  27. Minimal   Single occurrence of delayed menses (one cycle) that is otherwise regular

    Mild   Single occurrence of absent menses (one cycle) that is otherwise regular

    Moderate   Multiple occurrences of delayed or absent menses

    Severe   Total amenorrhea

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Form A–10

Menstrual Calendar

patient info 2

Instructions: Record the pattern of a woman’s menstrual cycle in a calendar format to indicate any irregularities and/or missed periods as the result of early pregnancy. Record initially at baseline during the physical exam and continue through the protocol (the form is cumulative).

Instructions for Completing the Menstrual Cycle Chart

  • Perform a pregnancy test prior to randomization on all female patients unless they are menopausal (no period for more than 1 year) or have had a hysterectomy or tubal ligation.

  • Find the correct month. Put an “X” in the box of the first day of the last period and put Xs in the following boxes through the last day of bleeding.

  • At baseline, do the same for the two prior menstrual cycles.

  • At each visit, put an “S” in the box of the day(s) where there has been any spotting since the last visit.

  • If it has been 35 or more days since the first day of the patient’s last period, do a pregnancy test at the visit. Also perform a pregnancy test if the patient has experienced any irregular spotting or bleeding between periods. Consider doing a pregnancy test every 4 weeks for any patient who does not have a consistent bleeding pattern (21- to 35-day cycles).

  • If the patient’s pregnancy test is positive, discontinue the medications. Pregnant women can continue to receive the counseling components of the treatment. In addition, refer the patient to an appropriate medical care provider regarding her pregnancy.

menstrual cycle chart

Instructions: Complete at each MM visit. This form is cumulative.

Week # / Sequence # MM Session Date
(mm/dd/yy)
Birth ControlType of Birth Control (See Codes at Bottom of page) Date of Late Menstrual PeriodPregnancy TestPregnancy Test Results Notes
YesNo(mm/dd/yy)Yes NoPosNeg
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 
/ /     / checkboxcheckbox  /     /   checkboxcheckbox 

Methods of Birth Control: 1=oral contraceptives; 2=hormonal (levonorgestrel) or surgical implants; 3=barrier plus spermicide; 4=abstinence; 5=other; 6=NA (menopausal—no period for > 1 year, hysterectomy, tubal ligation).

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Form A–11

Serious Adverse Event Report

patient info 3

Instructions: Complete this form whenever a patient has an experience that is known with certainty or suspected with good reason to constitute a threat to life or to cause severe or permanent damage. A serious adverse event is characterized by one or more of the following: it requires inpatient or prolonged hospitalization; it results in persistent or significant disability/incapacity; it results in death; it is life-threatening; or it is a congenital anomaly/birth defect. Drug misuse, drug overdose, and malignant tumors should also be regarded as serious, even if they do not result in the outcomes mentioned above. If there is a question about whether an event should be defined as serious, reference the FDA definition of a serious adverse event in the Federal Register. Once completed, notify the appropriate agencies within 48 hours.

1. a. Gender:   Femalecheckbox   Malecheckbox      b. Age: ____

2. Start of treatment: ____/____/______ month day year

3. Onset date of SAE: ____/____/______ month day year

4. Serious adverse experience (describe sign/symptom): ____________________________

5. Action taken (check all that apply):

   Yes         No

 checkboxesa) Medication
 checkboxesb) Dose reduced
 checkboxesc) Drug temporarily stopped (Date stopped: ____/____/______) month day year
 checkboxesd) Drug permanently stopped (Date stopped: ____/____/______) month day year
 checkboxese) Hospitalized
 checkboxesf) Other   Specify: _____________________________________________

6. Why was the event serious? (check one):

 checkbox 1) Fatal event
 checkbox 2) Life-threatening event
 checkbox 3) Disabling/incapacitating
 checkbox 4) Inpatient hospitalization
 checkbox 5) Hospitalization prolonged
 checkbox 6) Congenital anomaly
 checkbox 7) Cancer
 checkbox8) Result of an overdose

7. Relationship to drug (check one):

 checkbox 1) Not related
 checkbox 2) Possibly related
 checkbox 3) Not assessable

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Form A–12

Serious Adverse Event Followup Report

patient info 4

Instructions: Indicate date and any specific followup events or other clinical information relevant to the SAE reported on Form A–11.



















Signature:__________________________________________

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Form A–13

Medication Compliance Plan

Patient Info

I. Examine Patient’s History of Medication/Vitamin-Taking Practices

A. Determine Patient’s Experience With Pill-Taking

For each item below, check one response (Y/N). If “Yes,” indicate in the next column if patient was successful (Y/N) at taking the pills under the conditions specified. If “No,” that is, patient has not had the experience for longer than 1 week, check last column (N/A).

 Patient ResponseWas Patient Successful
YNYNN/A
1. Were you ever instructed or have you ever tried independently to take a pill(s) on a daily basis?checkboxcheckboxcheckboxcheckboxcheckbox
2. Were you ever instructed or have you ever tried independently to take four or more pills at one time on a daily basis?checkboxcheckboxcheckboxcheckboxcheckbox
3. Were you ever instructed or have you ever tried independently to take pills later in the day or at bedtime on a daily basis (in contrast to morning daily doses)?checkboxcheckboxcheckboxcheckboxcheckbox
4. Were you ever instructed or have you ever tried independently to take pills from blister cards?checkboxcheckboxcheckboxcheckboxcheckbox
5. Do you typically carry pills on or with you?checkboxcheckboxcheckboxcheckboxcheckbox
6. Do you usually take prescribed medications/vitamins until all pills are gone?checkboxcheckboxcheckboxcheckboxcheckbox

Notes:

B. Review Common Reasons for Pill Noncompliance (optional—to be used when appropriate per patient; strongly suggest use with all patients at initial session)

Ask the patient, “Have you experienced or could you see yourself not taking your medications during this treatment because of any of the following reasons?” (Circle all that apply)

1. Forgets to take or loses
2. Worries about side effects
3. Believes he/she is taking placebo
4. Has misinformation about medications (e.g., expects instant changes in drinking)
5. Has never liked taking pills—even aspirin
6. Desires to drink or “get high” medications
7. Tires of taking pills every day
8. Disagrees about having an alcohol disorder
9. Feels like he/she no longer needs medications

Tell the patient, “If any of these situations occur during treatment, please talk to me about it.”

Notes:

C. Discuss Successful Pill-Taking Strategies

List any pill-taking strategies that the patient uses/has used and indicate how successful they are/were. If the patient has no prior experience with pill-taking, have him/her think of strategies for remembering to take pills and list them here:



D. Summary and Recommendation

Based on patient responses on section A and notes, check the number that best applies.
___1. Experienced and successful with daily pill-taking. May not need a new plan.
___2. Experienced but has NOT been successful with daily pill-taking. May require a comprehensive plan with continual re-evaluation.
___3. No experience with daily pill-taking. Requires a basic plan for pill-taking.

II. Personalized Medication Compliance Plan

Record date: ___ /___ /20 ___ (month day year)    Note: This plan can be revised as needed.

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Form A–14

Pill Count (version used in COMBINE study)

pill count chart

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Form A–15

Date Entered__________
Staff Initials__________

Day 3 Clinician Phone Contact

patient info

Instructions: Complete this for all patients on the third day of Week 1. Complete also on the third day after a dose reduction. If you do not reach the patient on the third day, call on the fourth or fifth day.

1. Reason that patient was called:

 checkbox Week 1, day 3 phone contact
 checkbox Other:

2. Did you reach the patient?  checkboxYes checkboxNo

a) If no, did you reach the patient on day 4?  checkboxYes checkboxNo
b) If no, did you reach the patient on day 5?  checkboxYes checkboxNo

3. Is the patient taking the prescribed medications?

 checkbox a) Yes, as prescribed
 checkbox b) Yes, but not as prescribed
 checkbox c) No    Date stopped: __/__/____

4. Is the patient drinking?  checkboxYes    checkboxNo

5. Which of the following symptoms, if any, is the patient having? (Check all that apply)

 checkbox a) No side effects
 checkbox b) Nausea
 checkbox c) Vomiting
 checkbox d) Diarrhea
 checkbox e) Headache
 checkbox f) Anxiety
 checkbox g) Rash
 checkbox h) Other (specify)

6. What did you recommend? (Check all that apply)

 checkbox a) No change
 checkbox b) Dose reduction
 checkbox c) Pepto-Bismol®
 checkbox d) Vistaril®
 checkbox e) Change in time of dosing
 checkbox f) Tylenol
 checkbox g) Take with food
 checkbox h) Other (specify)

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Form A–16

COMBINE Study Fact Sheet for the Practitioner

Study Title

Combining Medications and Behavioral Interventions

Study Purpose

To examine the potential toxicity and acceptability of the administration of naltrexone and acamprosate both alone and in combination in approximately 1,375 alcohol-dependent patients.

Study Duration

The majority of COMBINE patients will receive 16 weeks of Medical Management (MM) and pharmacotherapy in a double-blind, placebo-controlled trial in one of three categories: (1) the combination of naltrexone and acamprosate; (2) each medication alone plus placebo; or (3) just placebo. One-half of the patients will also be given the Combined Behavioral Intervention (CBI). A small cohort (approximately 150 patients) will not receive pharmacotherapy but will receive CBI.

MM Session Schedule

Nine sessions total: Weeks 0, 1, 2, 4, 6, 8, 10, 12, 16.

Procedure for Dispensing Medications

A medical professional will dispense medications at MM sessions.

At the initial MM session, the MM clinician observes the patient taking his/her first dose of medication. The patient should receive the morning dose at the initial MM session no matter what time the appointment takes place. If the session is held in the morning, the patient is to take all three doses that day. If the initial MM session is held in the afternoon, the patient is to take the evening dose that evening, and the clinician should tape over the Day 1 afternoon dose on the blister card.

Note: The clinician may instruct patients to take their medication with meals.

Three days after the first MM session, the MM clinician should call the patient to inquire whether he/she is taking and/or tolerating the medication and then complete the Day 3 Clinician Phone Contact form (Form A–15). At all MM sessions, the clinician should support and encourage the patient in taking the medication. If the patient is having difficulty tolerating the run-up dose because of nausea and/or vomiting, the clinician should first encourage the patient to use Pepto-Bismol®. If the patient has already tried that without success, the clinician should proceed with the dosage reduction strategy outlined in the “Procedure for Reducing Dosage” section included in this fact sheet.

Emergency Cards

Patients will be given emergency cards to carry in their wallets stating that they are in a study involving investigative medications including naltrexone. The card includes suggestions on how medical practitioners should treat the patient in cases of cardiopulmonary resuscitation or if anesthesia is required; phone numbers for the patient’s physician, pharmacy, and 24-hour emergency assistance; and treatment beginning and ending dates. The patient’s significant other will also be given an emergency card.

Medication Packaging

Blister cards

Dosage Form

All study patients will take four tablets in the morning, two tablets at midday, and two tablets in the evening of some combination of active medication or placebo.

Note: Patients should be advised not to crush acamprosate pills because this can reduce the pill’s bioavailability and increase the gastrointestinal (GI) side effects.

Timing of Doses

If a patient misses a dose of acamprosate, he/she should not take it simultaneously with the next scheduled dose; there should be a minimum of 2 hours between doses. If this is not feasible, the clinician should instruct the patient not to take the skipped dose but to wait until the next scheduled dose and take only that dose.

If a patient misses the morning dose, the clinician should instruct him/her to replace the midday dose with the morning dose.

It is permissible to administer naltrexone BID when evidence of side effects dictates twice-a-day dosing.

Procedure for Handling Side Effects

The clinician should handle side effects by doing the following:

  1. Listen to patient complaints seriously.

  2. Rule out any serious concomitant medical disorders.

  3. Rule out serious drug-related adverse experiences as evidenced by such symptoms as yellow eyes, light-colored stools, dark urine, or severe abdominal pain.

  4. Ask the patient if he/she has recently used alcohol or other drugs. Rule out alcohol, opiate, or other drug use and/or withdrawal as contributors to presenting complaints.

  5. Ascertain what strategies the patient has used to manage the presenting symptom(s) and the degree of relief obtained, if any. Refer the patient to Patient Instructions for Managing Side Effects (Form C–5).

  6. Reassure the patient that adverse drug experiences tend to be transient and resolve within 12 to 72 hours.

  7. Tell the patient that the first steps in dealing with adverse experiences should be to take an over-the-counter medication such as Pepto-Bismol (for GI side effects) or acetaminophen (for headache); adjust the time of the dosing (e.g., take naltrexone at night); and/or take the medication with meals. If this is unsuccessful or insufficient, try the dose reduction strategy as detailed under “Procedure for Reducing Dosage,” below. The following step, if necessary, should be to use prescription medication (i.e., hydroxyzine) (see step #8).

  8. Use hydroxyzine (Vistaril®) as a treatment for several side effects; prescribe it for a maximum of the equivalent of 10 days dosage. If the patient discontinues Vistaril and side effects reappear, prescribe Vistaril again; however, the patient must be off Vistaril for at least 3 days before taking it again.

Procedure for Reducing Dosage

The clinician should do the following for patients reporting nausea, vomiting, diarrhea, dizziness, nervousness, anxiety, and insomnia:

  1. Tell the patient that the doses of one medication will be reduced initially, and if this is not sufficient, the dose of the other medication will be reduced.

  2. Tell the patient to take only one acamprosate in the morning and one in the afternoon, rather than taking two in the morning and two in the afternoon.

  3. Reduce the patient’s dose of naltrexone before reducing the acamprosate dose if the patient’s bilirubin level increases by 50 percent over baseline values and is still within allowable limits for patient to stay in the study. If the patient continues to suffer from side effects when the naltrexone dosage has been reduced to 50 mg, reduce the dosage to 25 mg. However, if the patient cannot tolerate the 25 mg dose of naltrexone, discontinue all study medications.

  4. Reduce the patient’s dose of naltrexone to 25 mg for all side effects, including elevated bilirubin, if he/she cannot be maintained on the 50 mg dose. Attempt to increase the dose of naltrexone whenever possible, but if the patient cannot tolerate the increase, he/she can remain on a maintenance dose of 25 mg of naltrexone.

  5. Call the patient 3 days after making a dosage reduction. If the patient is doing better, he/she can stay with this dosage regimen. If the patient still experiences symptoms, tell him/her to take only one naltrexone in the morning rather than two. Complete the Day 3 Clinician Phone Contact form (Form A–15).

  6. At the next MM visit, encourage the patient to start increasing the medication dosage, beginning with naltrexone. If the patient is able to tolerate it, increase the acamprosate dose 3 days later. If the patient is unable to tolerate a second dose increase, recommend going back to the reduced dosage level. If the patient is reluctant to go back to the full dose, assure him/her that if the side effects return at the full dose, he/she may go back to the lower dose.

Procedure for Retitration

Acamprosate will not be titrated. These procedures refer to naltrexone only. Patients who have been off study medications for 4 or more weeks may be retitrated at the discretion of the clinician. Although patients who have been off medication for less than 4 weeks probably do not need retitration, the procedure may be used anyway.

If a patient is removed from study medication for any length of time, the retitration would be 2 days at 50 mg naltrexone per day, and then the patient will resume the usual dose of 100 mg of naltrexone a day. This will occur at the discretion of the study medical clinician; if a patient did not experience any side effects while taking the study medication previously, the medical clinician may decide not to retitrate.

Patients who are retitrating will be instructed to take only 1 pill of naltrexone per day for the 2 days of 50 mg dosing.

If the patient is not tolerating the study medication, he/she could be retitrated on 25 mg of naltrexone (half of 1 pill) at the discretion of the medical clinician.

Management of Adverse Effects

The clinician should manage adverse effects by doing the following:

Diarrhea

  1. Suggest that the patient take Pepto-Bismol® if he/she has not already done so. If this does not work in 1 to 2 days, proceed to #2.

  2. Reduce the dose of the study medication as described in the section “Procedure for Reducing Dosage.”

Nausea

  1. Suggest that the patient take Pepto-Bismol if he/she has not already done so. If this does not work in 1 to 2 days, proceed to #2.

  2. Reduce the dose of the study medication as described in the section “Procedure for Reducing Dosage.”

  3. If the patient continues to experience nausea for 3 days after the doses of both medications have been reduced, offer a prescription for hydroxyzine pamoate (Vistaril®), 25 mg to 50 mg, after checking for allergies; instruct the patient to take Vistaril 30 minutes before taking the next dose of the study medication. Patients can take up to 50 mg of Vistaril per day, either all in the morning, all in the evening, or half in the morning and half in the evening. Some patients will do better taking the Vistaril in the morning because they may experience worse nausea in the morning. However, Vistaril can be sedating in some people, so balance these two considerations in deciding about the timing of the Vistaril dosing. Note on the Concurrent Medications form (A–3) if you have prescribed Vistaril.

  4. If steps #1 through #3 are not successful, hold all doses of study medication, and proceed with the steps under “Vomiting.”

Vomiting

  1. Discontinue study medication until the patient is no longer nauseated.

  2. When the patient has a morning on which he/she experiences no nausea, check for allergies and, if possible, prescribe 25 mg or 50 mg of Vistaril to be taken 30 minutes before taking a dose of study medication (see #3 in the “Nausea” section for further details about Vistaril dosing).

  3. Reduce the dose of the study medication as described in the section “Procedure for Reducing Dosage.”

Dizziness, Nervousness, Anxiety, Insomnia

Prescribe 25 mg or 50 mg of Vistaril.

Headaches

Advise the patient to take over-the-counter medications such as acetaminophen.

Dermatologic Symptoms

  1. If the patient experiences localized rash or pruritis, no intervention is required; explore other etiology.

  2. If the patient experiences generalized erythema and/or macular or maculopapular rash and/or pruritis, without other etiologic explanation:

  3. a) Discontinue vitamin B supplements.

    b) Try symptomatic treatment with oral antihistamines (e.g., hydroxyzine hydrochloride [Atarax®], 25 mg t.i.d.) and topical corticosteroids (e.g., triamcinolone acetonide cream) for up to 1 week.
    (i.) If rash/pruritis improves or disappears, continue the study drug.
    (ii.) If rash/pruritis worsens, the rash is atypical (i.e., other than maculopapular), the rash is urticarial, or if there is mucous membrane involvement, in the absence of another etiologic explanation, discontinue study drug and refer the patient to a dermatologist for evaluation and possible biopsy. (Note: Code as an adverse event, and prepare other appropriate documentation.)

Procedure for Handling Abnormal Lab Values

The clinician should handle abnormal lab values as follows:

Elevated Liver Enzymes: A patient with an ALT/AST greater than five times the normal rate will need to have ALT/AST repeated within 1 to 2 weeks; if it is still greater than five times the normal rate after that, stop the patient’s medication. If the repeat values are less than five times the normal rate but are still elevated, monitor the patient using clinical judgment. A study physician will evaluate the patient if he/she has a total bilirubin above 50 percent baseline level but is still within normal range to determine whether he/she should discontinue study medication.

If a patient’s bilirubin levels increase by 50 percent over the baseline values but still remain within the normal range, reduce the naltrexone dose first, rather than run the risk that the patient’s bilirubin levels will continue to rise and meet the threshold for the patient’s withdrawal from the study medications altogether. As when handling the patient’s side effects, reduce the naltrexone dose to 25 mg if the patient cannot tolerate the 50 mg dosage. However, if the patient cannot tolerate the 25 mg dose of naltrexone, discontinue all study medications.

Patients whose total bilirubin is greater than 10 percent above the upper limit of normal will be taken off the study medication immediately.

Renal insufficiency: A study physician will evaluate patients whose serum creatinine level is 1.3 or 1.4 to ascertain whether they should discontinue study medication. However, if a patient has a creatinine cut-off of 1.5, he/she should be removed from the study medication.

GGT: If a patient’s GGT is elevated, the responsible medical clinician will determine the course of action, which may include more frequent monitoring of liver function tests.

Week 16 Lab Results

The clinician providing feedback for Week 16 lab results should contact the patient after treatment has ended, relaying the lab results by phone if the patient is not available in person.

Procedure for Adding Concurrent Medications

Patients should be regularly reminded to report any concurrent medications they are taking, including over-the-counter preparations, vitamins, and so on. Because acamprosate is eliminated exclusively by the renal route, patients should avoid nephrotoxic drugs, such as aminoglycoside antibiotics, during this study as well as diuretics, which affect elimination of acamprosate. Patients can intermittently take nonsteroidal anti-inflammatory drugs, which also affect the elimination of acamprosate, but they should avoid these drugs when possible. Because naltrexone is an opiate antagonist, patients should avoid narcotics and other opioid drugs during the study, as well as Mellaril®, which has been associated with an adverse interaction with naltrexone.

If a patient begins to take a concurrent medication on the disallowed list, he/she should be discontinued from study medication immediately.

Drugs not allowed as concomitant medications

  • Cis-retinoic acid (Accutane®)
  • Alphamethyl Dopa (Aldomet®)
  • Anorexics (e.g., over the counter, amphetamines, phenylpropanolamine, Dexatrim®)
  • Antiarrhythmics (e.g., quinidine, digoxin [Lanoxin®], disopyramide [Norpace®])
  • Anticoagulants (e.g., coumadin [Warfarin®])
  • Anticonvulsants (e.g., valproic acid [Depakote®], gabapentin [Neurontin®], phenytoin [Dilantin®], carbamazepine [Tegretol®])
  • Antidepressants (e.g., fluoxetine [Prozac®], sertraline [Zoloft®], paroxetine [Paxil®], trazodone [Desyrel®], desipramine [Norpramin®])
  • Antipsychotics (e.g., haloperidol [Haldol®], risperidone [Risperdal®], olanzepine [Zyprexa®], fluphenazine [Prolixin®], perphenazine [Trilifon®])
  • Antiretrovirals (Combivir®, Epivir®, Norvir®, Retrovir®)
  • Buprenorphine (Buprenex®)
  • Bupropion (e.g., Wellbutrin®, Zyban®)
  • Buspirone (Buspar®)
  • Chemotherapeutic agents for cancer
  • Cholestyramine
  • Disulfiram (Antabuse®)
  • Duradrin
  • Flexeril
  • Herbal supplements with GABA properties (e.g., Kava, GABA, or DHEA) or antidepressant properties (e.g., St. John’s Wort, L-Tryptophan, 5-HTP)
  • Herbal supplements containing ephedra
  • Methotrexate
  • Monoamine oxidase inhibitors (e.g., phenelezine [Nardil®], tranylcypromine [Parnate®])
  • Mood stabilizers (e.g., lithium [Eskalith®, Lithobid®])
  • Opioid analgesics (e.g., morphine, codeine, oxycodone [Percodan®, Percocet®], hydrocodone [Vicodan], propoxephine [Darvon], tramadol [Ultram®])
  • Ondansetron (Zofran®)
  • Oral corticosteroids (e.g., prednisone, dexamethasone)
  • Psychostimulants (e.g., amphetamines [Dexadrine®], methylphenidate [Ritalin®])
  • Reserpine
  • Robaxin
  • Sedatives (antihistamines are okay) (e.g., barbiturates, benzodiazepines, hypnotics [Ambien®]).

Drugs allowed as concomitant medications

  • Acyclovir
  • Allopurinol
  • Antiasthma agents (e.g., inhalers, B-agonists, theophylline), antibiotics
  • Anti-inflammatory drugs (e.g., aspirin, ibuprofen [Motrin®, Advil®], naproxen [Naprosyn®, Aleve®])
  • Aspirin (81 mg/day regimen for cardiac disease)
  • Colchicine
  • Inhaled steroids
  • Lipitor®: permitted if on a stable dose (3 months). Lipitor should not be started and the dose should not be changed during the trial.
  • Melatonin
  • Nicotine replacement therapy (e.g., gum, inhaler, or patch [no Zyban®])
  • Proton pump inhibitors (pantoprazole)
  • Sildenafil.
Drugs allowed as concomitant medications for chronic use only (consistent use for 1 month prior to randomization and dose stabilized, or if the medication is started postrandomization)
  • Antianginal agents: nitrates
  • Antihypertensives (e.g., doxazosin [Cardura®], terazosin [Hytrin®], Tenormin®, diltiazem [Cardizem®], lisinopril [Zestril®], enalapril [Vasotec®], metoprolol [Lopressor®])
  • Calcium channel blockers (e.g., nifedipine, verapamil, nimodipine)
  • Clonidine (Catapres®)
  • Diuretics (e.g., hydrochlorothiazide [Diuril®, Dyazide®], spironolactone [Aldactone®])
  • H2 Blockers (e.g., ranitidine [Zantac®] [No cimetidine])
  • Hormones and oral contraceptives (estrogen [Premarin®], progesterone)
  • Insulin
  • Oral hypoglycemic agents
  • Thyroid supplements.
Drugs allowed as concomitant medications for episodic use only
  • Analgesics, nonnarcotic (e.g., aspirin, acetaminophen [Tylenol®], ibuprofen [Motrin®, Advil®])
  • Antacids (e.g., magnesium hydroxide-aluminum hydroxide [Maalox®, Mylanta®], calcium [Tums®])
  • Antidiarrheal preparations (not opioid-based)
  • Antihistamines (e.g., diphenhydramine [Benadryl®], hydroxyzine [Vistaril®], Claritin®, cetrizine [Zyrtec®])
  • Antimigrain (e.g., Imitrex®, no Fiorinal®)
  • Antinausea agents
  • Cough/cold preparations (nonnarcotic cough suppressants)
  • Laxatives.

Procedure for Managing Patients Who Request Treatment Outside COMBINE

The clinician should follow the steps below for problematic patients:

  1. Employ MM strategies, such as suggesting the patient attend more AA or Al-Anon meetings.

  2. Advise patients requesting additional formal help that it is common for ancillary problems such as marital or parenting issues to arise during the course of treatment and that such problems might eventually be resolved or reduced if they maintain abstinence. Review these matters again at the end of the patient’s treatment, but focus primarily on MM-related concerns (i.e., medication compliance, side effects, and support for abstinence).

  3. The project coordinator (PC) and principal investigator (PI) should be involved if clinical deterioration is an issue.

  4. If a patient’s ancillary problems persist, refer the patient to the PC so he/she can provide the patient with referral sources.

  5. If the patient is struggling with concrete problems such as housing, unemployment, or financial matters, make a case management referral to other formal treatment(s). (This is consistent with the MM model because such referrals would help provide the necessary foundation to support the patient’s ongoing abstinence.)

Patients who become involved in formal adjunctive treatment will not be removed from the treatment protocol. However, the clinician should document this involvement in the Research Records.

Procedure for Handling Emergent Psychiatric Symptoms

This is site-specific, based on good clinical practice protocols designed to ensure patient safety at each institution.

Procedure for Handling Increased Drinking

Based on the treatment goals of total abstinence and decreased drinking, patients who require a more intensive treatment setting at any point after randomization will be categorized as “treatment failure.” Such patients will be discontinued from further study participation. The clinician will document the reason for premature discontinuation of such patients as “needed more intensive treatment” in the Research Records.

Medication Noncompliance

If the patient takes any dose not as prescribed, the clinician should document it as noncompliance in the Research Records.

Treatment Noncompliance

Inactive Status

A patient will be designated “inactive” if he/she misses three consecutive scheduled sessions or does not attend a visit in 1 month (whichever comes first), regardless of the reasons for missing the sessions. Also, a patient who directly expresses his/her unwillingness to reschedule subsequent treatment sessions will be declared “inactive.”

When a patient is designated inactive in MM, the MM clinician will send him/her a formal note confirming his/her decision not to attend or resume MM sessions and/or take trial medication. The note will include a message encouraging the patient to return to MM and/or resume trial medication at a later time if desired. The clinician will send a followup letter 2 weeks later, reiterating this message.

When a patient is designated inactive in both CBI and MM, the MM clinician will send a formal note confirming the patient’s decision not to attend or resume MM sessions and/or take trial medication (the CBI therapist will send a separate note). The note will include a message encouraging the patient to attend future MM sessions and/or to resume trial medication if desired. The MM clinician will send a followup letter 2 weeks later, reiterating this message.

The clinician should document in the Research Records the patient’s inactive status as such:

  1. The patient discontinues study medications but continues to go to MA sessions.

  2. The patient discontinues medications and MA.

Note whether it was the clinician’s or the patient’s decision to discontinue study medications or MA and indicate reasons for discontinuation of study medication. Indicate also if patient continued or not with CBI, where applicable.

Preparing for the Final MM Session

As soon as the clinician feels he/she has engaged the patient in the treatment and has had several productive visits (e.g., six to seven visits), the clinician needs to begin to anticipate, with the patient, what will occur at the end of the research treatment period. Before the final visit, the clinician should discuss with the patient what type of treatment, if any, the patient may want to pursue following completion of the research treatment trial. The clinician should inform the patient that he/she cannot continue treatment with the clinician after the scheduled treatment ends. Since the MM clinician in a double-blind study will not know which active medication, if any, the patient has taken, it is difficult for this clinician to clearly recommend a particular course of treatment in the future. Thus, the clinician should ask the patient about his/her thoughts about continuing treatment (or not), and then use best clinical judgment in discussing this issue and in recommending future treatment. The clinician should consider the patient’s current clinical condition and wishes when making this recommendation.

If the patient is assigned to both MM and CBI, the clinician and therapist should coordinate the referral process prior to the last session and not provide contradictory information to the patient.

Reasons for Discontinuation of Study Medications

Below is a list of reasons why the clinician should stop the patient’s medications:

  1. The patient has a severe and/or serious adverse experience or severe intercurrent medical/psychological/surgical event.

  2. There was an appearance of an exclusion criterion not considered attributable to study medication (e.g., pregnancy).

  3. The patient’s AST/ALT is greater than five times normal after the test has been repeated.

  4. The patient’s total bilirubin is greater than 10 percent of the upper limit of normal.

  5. The patient’s serum creatinine level is 1.5 or greater.

Reasons for Premature Study Discontinuation

[Note: An effort must be made to have all patients who prematurely discontinue study participation undergo an end-of-treatment evaluation (Visit 9).]

Below is a list of reasons why patients could leave the study before they finish treatment:

  1. The patient required more intensive treatment during the active treatment phase, so his/her status is considered “treatment failure.”

  2. The patient had reasons other than “treatment failure” (e.g., work commitments do not permit keeping appointments, relocates).

  3. The investigator decides to discontinue patient participation prematurely for a reason other than “treatment failure.”

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