A PROSPECTIVE, RANDOMIZED PILOT STUDY OF HIGH, MEDIUM OR LOW THC-CONTENT SMOKED MARIJUANA ON WEIGHT LOSS IN PERSONS WITH HIV-RELATED WASTING SYNDROME VERSUS DRONABINOL (DELTA-9-TETRAHYDROCANNABINOL, MARINOL, ROXANE LABORATORIES)

A community-based clinical trial conducted by the Community Consortium, University of California, San Francisco

IND # 43,542

Principle Investigator: Donald I. Abrams, M.D.

PURPOSE

To conduct a pilot study evaluating high, medium and low potency smoked marijuana or dronabinol in stimulating appetite and reducing weight loss associated with HIV-related wasting syndrome.

BACKGROUND/RATIONALE

With widespread use of antiviral agents and prophylaxis for opportunistic infections, patients with HIV disease are surviving, often times without developing the frequently recognized opportunistic infections characteristic of AIDS. The wasting syndrome has become an increasingly important clinical manifestation diagnosed in patients with advanced stages of HIV disease.(1,2) After ruling out the possibility of an underlying opportunistic infection, wasting syndrome is a diagnosis of exclusion which is usually characterized by significant weight loss (greater than 10% of body weight) and some permutation of fevers, night sweats, and/or diarrhea. The underlying pathophysiology of the wasting syndrome remains unclear. Inflammatory cytokines such as interleukin-1 and tumor necrosis factor have been implicated.(3,4,5) It is becoming more apparent that the cachexia associated with the HIV-related wasting syndrome is in and of itself likely to potentiate immune deficiency and be an independent risk factor for increased mortality.(6,7) Nutritional impairment may also hamper the response to therapy and increase the risk of treatment related toxicities.

Multiple pharmacologic agents are currently being evaluated in the treatment of HIV-related wasting.(8,9) Similar to the situation of anorexia and cachexia in patients with malignant disease, dronabinol (delta-9-tetrahydrocannabinol, Marinol) has shown activity as an appetite stimulating agent in patients with HIV-related wasting. (9,10,11,12) Marinol was approved by the Food and Drug Administration in December, 1992 as the first agent targeted to treat the anorexia associated with weight loss in patients with AIDS.

Dronabinol was initially developed as an antiemetic in cancer patients undergoing chemotherapy. In addition to alleviating nausea, an independent effect of increased food intake was also reported.(13) A retrospective analysis of dronabinol use in patients with AIDS-related cachexia showed patients experiencing a mean weight gain of 0.6 kilograms/month after initiating dronabinol therapy for the wasting syndrome.(9) The weight gain was not felt to be secondary to fluid retention. Treatment was well tolerated by most patients who also reported improvement in their mood and sense of well being, without euphoria. A subsequent dose response study demonstrated that 2.5 mg of dronabinol two to three times per day produced a greater increase in body wight than 5 mg orally two to three times per day.(9) The recommended dose of dronabinol in the package label suggests commencing with 2.5 mg twice daily before lunch and dinner.

Results of a larger placebo controlled trial were reported at the Eighth International Conference on AIDS.(14) In this multicenter study, 139 patients with AIDS and greater than 2.5 kilograms loss from their usual body weight were randomized to receive either dronabinol 2.5 mg bid or placebo for six weeks after which they became eligible to continue on an open label study. Patients were evaluated with regard to appetite, mood and nausea using visual analog scales completed periodically during the trial. Clinical follow-up for weighing and physical examination was obtained every two weeks during the randomized portion and monthly during the open label study. The study was hampered by a large percentage of patients in both arms who were unevaluable for a number of different reasons. However, a statistically significant improvement in appetite and mood and a decrease in nausea were seen in patients receiving drug compared to placebo during the blinded phase. By the end of ten weeks of treatment, 39% of the patients initially on dronabinol had gained 2 kilograms or more. Such a weight gain was not perceived in the placebo group until they had been on open label dronabinol for at least two months. Treatment was generally well tolerated, with five patients receiving dronabinol and four receiving placebo discontinuing therapy due to side effects attributed to study medications. A significant number of patients using dronabinol off study have reported side effects which are unpleasant and limit their ability to tolerate the drug, even at reduced doses.

Anecdotal reports have long been forthcoming from recreational users of marijuana suggesting an appetite stimulating effect. This situation has led to a recommendation that smoked marijuana be considered as a possible alternative to oral dronabinol. Clinical trials have demonstrated the usefulness of smoked marijuana in the treatment of nausea and vomiting associated with chemotherapy in patients with malignancies.(15) A controlled study compared body weight and caloric intake of twenty-seven marijuana users to ten control subjects for twenty-one days on a hospital research ward setting.(16) The marijuana smokers were found to eat more and gain weight while the controls remained stable. Upon cessation of smoking, the marijuana smokers immediately began to eat less. In a trial, with individuals serving as their own controls, nine subjects smoked two to three placebo cigarettes daily and then switched to marijuana cigarettes of average potency.(17) Their food intake significantly increased, largely secondary to increased snacking rather than the consumption of larger meals during the period of marijuana use.

Use of marijuana by people with AIDS has been limited due to a lack of its availability as an approved pharmaceutical substance. After the death of Kenny Jenks, a patient who had voluntarily appeared on national media as a spokesperson for the medical utility of smoked marijuana, there are no longer any AIDS patients in the country receiving supplies of marijuana for HIV-related wasting syndrome through the FDA's Compassionate Use Program. Numerous other people with AIDS, despite their inability to obtain legal supplies, are also now choosing to self-medicate with smoked marijuana. Many patients report the ability to self-titrate their doses, and thus decrease side effects, as the main attraction of using smoked marijuana over pharmaceutically available dronabinol. Others say that smoking marijuana helps them more than dronabinol to eat more food. It is felt that a pilot study comparing the safety and efficacy of three potencies of smoked marijuana to dronabinol could help determine whether future studies of the medical use of smoked marijuana should be conducted for this indication.

STUDY OBJECTIVES

Primary Objective

To compare the changes in weight over the three month period of therapy in AIDS patients with the wasting syndrome receiving high, medium or low potency smoked marijuana or dronabinol.

Secondary Objectives

• To compare changes in lean body mass among patients randomized to high, medium or low potency smoked marijuana or dronabinol
• To compare the change in CD4 lymphocyte counts among patients randomized to high, medium or low potency smoked marijuana or dronabinol
• To compare the quality of life among patients randomized to high, medium or low potency smoked marijuana or dronabinol
• To compare the incidence of adverse experiences among patients randomized to high, medium or low potency smoked marijuana or dronabinol

STUDY ENDPOINTS

Primary Endpoint

• Change in weight 3 months from baseline

Secondary Endpoints

• Rate of change in weight (per month)
  
• Change in lean body mass measured by bioelectric impedance
  
• CD4 cell count
  
• Change in appetite
  
• Quality of life
  
• Adverse experiences
  
• Permanent discontinuation of study medication

METHODOLOGY

STUDY DESIGN

Single center, prospective, double-blind, randomized pilot study with patients participating for three months. Patients will be randomized into one of four groups receiving either high, medium or low potency smoked marijuana or open label dronabinol. There will be ten patients in each group for a total sample size of 40 patients.

RANDOMIZATION

Randomization will be completed in accordance with standard procedures. Patients with and without prior exposure to smoked marijuana will be stratified in equal numbers into all of the experimental treatment arms.

SAMPLE SIZE AND STATISTICAL CONSIDERATIONS

This experiment is a pilot study. The sample size need not be large enough to detect a clinically significant weight difference between the groups. However, the sample size should be large enough to gather useful information abut the variability of weight gain in response to high and low potency smoked marijuana sufficient for the design of a subsequent study large enough to detect clinically significant differences in weight between the groups. There will be ten patients in each of the four arms for a total of 40 patients enrolled. The variability of weight gain in response to dronabinol has previously been determined to roughly equal a standard deviation of 4.5 kg.

PATIENT SELECTION

It is hoped that most patients who participate in this study will, barring complications, continue their participation until the termination of the study regardless of whether or not they remain on assigned study treatment. Enrolled patients should be willing and able, in the clinician's opinion, to comply with the treatment regimen and clinical management issues as outlined in the protocol. The patient must meet all of the inclusion criteria and may not have any of the conditions that would exclude her/him from the study. They should have a Karnofsky score > 60 (indicating that they do not require considerable assistance and frequent medical care) and a perceived life expectancy of at least six months.

Participating patients should practice an adequate method of birth control while on study medication.

INCLUSION CRITERIA

1. Evidence of HIV infection including any of the following:
   • Documented positive serology for HIV infection

     OR

   • Documented history of AIDS as defined by the "Revised Case Definition for AIDS Surveillance Purposes" (1993)
     
     
2. Clinician diagnosis of wasting which should include a documented involuntary loss of 10% or more of body weight over the past twelve months not attributable to another cause
3. Documented history of weight recorded for at least two months prior to entrance into the study
4. Age &gt= 18 years.
5. Ability and willingness to give informed consent

    

EXCLUSION CRITERIA

1. Pregnancy or breast feeding
2. Chronic use (more than three times a week) of marijuana or dronabinol within the past 30 days
3. Currently receiving parenteral nutritional therapy
4. Treatment with megestrol acetate (Megace) within 30 days
5. History of adverse reaction or hypersensitivity to either of the study medications or sesame oil
6. Patients with &gt= grade 1 AIDS dementia complex
7. Patients with a history of ongoing substance abuse
8. Patients with a history of cardiovascular disease

    

TREATMENT PLAN

STUDY MEDICATION: SUPPLY, DOSAGE AND ADMINISTRATION

Dronabinol (Marinol, Roxane Laboratories) will be provided in 2.5 and 5.0 mg tablets. Patients will begin treatment at a dose found to be efficacious in prior studies and recommended by the manufacturer ( i.e. 2.5 mg po bid before lunch and dinner). Patients will be advised to self-titrate their dose depending on the development of side effects. If patients at a dose of 2.5 mg. bid are tolerating therapy and do not appreciate an increase in appetite they may increase their dose to 5 mg. po tid. Patients will keep a daily record of the quantity and timing of their use of dronabinol.

Patients will be provided with individually measured two gram packages of either high (7.57%) medium (3.95%) or low (1.79%) potency marijuana. The marijuana will be supplied by the National Institute on Drug Abuse (NIDA). [Note: NIDA has refused to supply marijuana to this study, effectively preventing it from taking place. A revised version of this protocol is being submitted to the National Institutes of Health for its January 1, 1996 deadline. NIDA has indicated that if the NIH approves the study, NIDA will reconsider its decision not to provide marijuana to this research project. A decision regarding NIH approval is expected by June 1996] The marijuana will be sterilized prior to its distribution to eliminate any contamination with aspergillus.

Patients randomized to the inhaled treatment arm will be provided with a waterpipe. Patients will be instructed to smoke 2-4 deep inhalations 1/2 to 1 1/2 hours prior to lunch and dinner. Patients will self-titrate their dose with the expectation that they will smoke between 0.5 gm and the maximum allowed 2.0 gm per day. A maximum limit of two grams total of marijuana per day will be placed on the consumption of marijuana to limit the chance of diversion of marijuana to people who are not enrolled in the study. Patients will be asked to quantify their daily use of marijuana with the submission of their bi-weekly three-day dietary history. Patients who discontinue the study prior to conclusion will be required to return their unused portion of marijuana.

All study drugs will be available through the investigational pharmacy located in the AIDS program at San Francisco General Hospital. Medications will be handled in the manner suitable for Schedule 1 agents. Clinical Research Nurse staff will monitor drug distribution using standard drug accountability monitoring.

CONCOMITANT MEDICATIONS

Baseline and routine follow-up recording of medications will be conducted in accordance with standard procedures. There are no known significant drug interactions with either study medication. Other drugs for HIV-related wasting, specifically megestrol acetate (Megace) may not be taken during the study, otherwise there are no restrictions for concomitant medications.

BASELINE SCREENING AND ENROLLMENT

1. A baseline history and clinical evaluation will be performed within 30 days prior to randomization.
2. Baseline history will include use of marijuana or dronabinol.
3. Body weight will be measured within 7 days prior to randomization.
4. The patient's maximal body weight, documented over the last twelve months, will be recorded.
5. The patient's lean body mass will be measured by bioelectrical impedance.
6. The patient's body weight two months prior to randomization should be available.
7. A negative pregnancy test will be obtained on women of childbearing potential.
8. Spirometry will be performed at baseline.
9. A three day diet diary will be recorded by the patient at the time of enrollment prior to randomization.
10. A Quality of Life Questionnaire will be completed by the patient and a health care provider. This questionnaire will include tests for mood, depression and appetite.

PATIENT MONITORING AND FOLLOW-UP

Patients will be seen in the clinic/office of their primary provider for initial evaluation. They will report to the clinical research nurse at the General Clinical Research Center at San Francisco General Hospital ever two weeks for clinical evaluation, data collection and drug distribution. Information to be collected at each visit will include:

1. A completed three day diet diary brought to the appointment
2. History of adverse experiences
3. Assessment of patient compliance with study medication including an estimation of utilization and method of inhalation for marijuana, patients' guess of which THC content marijuana they are using
4. Pulmonary review of symptoms and chest auscultation
5. Quality of Life Questionnaire to be completed with clinical research nurse at time of visit
6. Body Weight
7. Lean body mass by bioelectrical impedance
8. Appetite assessment via visual analog scale
9. Lymphocyte subset analysis (week 8 and 12 or at completion of study)
10. Spirometry at week 12 or completion of study

CLINICAL MANAGEMENT ISSUES

INSTRUCTION IN USE OF STUDY MEDICATIONS

All subjects will be given information about the range of subjective effects they may experience from either oral dronabinol or smoked marijuana. In addition, subject will receive their fist dose of the study medication under the supervision of study personnel. They will be observed in the General Clinical Research Center at San Francisco General Hospital for their first dose. Subjects will be given in individualized instructions in how to use a water pipe. how to self-titrate their dose, and how to relax if the subjective effect of the marijuana or dronabinol are in any way disturbing or disorienting. Blood pressure and heart rate will be monitored during the initial exposure to the study medication. Subjects whose initial experience is difficult will be required to self-administer their subsequent doses under supervision until the study personnel and subject agree that such training is no longer necessary. Subjects will be instructed to smoke only at home with the water pipe unless absolutely necessary. At the conclusion of participation in the trial, all individuals who underwent instructions in smoking will be given a written form to evaluate the quality of the training sessions. Suggestions about improving the usefulness of the training sessions will be sought.

DRUG TOXICITY AND GRADING

Patients will be closely monitored for signs and symptoms of drug toxicity. Assessment of adverse experiences and reporting of Grade 3 and greater toxicities will be done at the follow-up visits. For toxicities that require the study therapy to be temporarily or permanently discontinued, relevant clinical and laboratory evaluations will be repeated as needed until there is a final resolution or stabilization of the toxicity. Plasma and/or urine THC screens will be performed on patients who develop an adverse effect that may be related to study doing toxicity.

Symptoms and laboratory findings should be graded using the standard Toxicity Table. Grade 3 or higher adverse experiences encountered during the course of the study will be recorded on standard case report forms. Any life-threatening event or death that occurs on the study must be reported immediately to the principal investigator and forwarded to the FDA.

Common Toxicities from Study Drugs

Side effects of dronabinol include a cannabinoid dose-related "high" (easy laughing, elation and heightened awareness). The most frequently reported adverse experience in patients with AIDS involved the CNS and were reported by 33% of patients receiving dronabinol. Events reported with an incidence of 3-10% include euphoria, dizziness, somnolence, paranoid reaction, nausea and vomiting.

Smoking marijuana may be associated with cough and bronchospasm. Side effects of smoked marijuana include alterations in consciousness and mood, anxiety, euphoria, drowsiness, depression, disorientation, paranoia, confusion, tachycardia, palpitations, dizziness, syncope, injected conjunctivae and xerostomia. Frequent marijuana smoking may be associated with an increase risk of respiratory illness.(18,19,20)

Adverse Experiences

All adverse experiences encountered during the course of the study will be recorded on standard case report forms. Any life-threatening event or death that occurs on the study drug must be reported immediately to the Community Consortium. Donald Abrams, M.D. will be responsible for reporting the information to the Food and Drug Administration and the Research Advisory Panel of the State of California. The local institutional review board will be apprised by Community Consortium personnel of any serious or life-threatening adverse experiences as early as possible per routine established protocol.

Criteria for Discontinuation of Study Medication

1. Patient intolerance
2. Patient non-adherence to protocol including diversion of study medication
3. Grade IV toxicity
4. Patient of physician decision

Study Discontinuation

At the termination of the trial, patients will be requested to return all unused medications. Patients will undergo repeat spirometry. Patients who have completed the twelve weeks on the dronabinol arm of the study will be offered the option of participating in a twelve-week open label study of the use of high potency smoked marijuana. Patients who desire dronabinol treatment after the termination of their participation in the trial can obtain it by prescription from their primary care provider.

EVALUATION

DATA ANALYSIS

The goals of the data analysis are:

1. To evaluate changes in weight, dietary intake, perceived quality of life, lean body mass, and lymphocyte subset counts in response to smoked marijuana and dronabinol in the treatment of weight loss in HIV-related wasting syndrome.
2. To assess the impact of smoked marijuana on pulmonary functions as measured by office spirometry at baseline and at study conclusion.

STATISTICAL METHODS

Associations between baseline characteristics, treatment, and the outcome variable will be analyzed using a variety of statistical techniques. These include non-parametric analysis of variance, Spearman rank correlation, and exact tests utilizing contingency tables. Results will be reported for univariate as well as multivariate analyses controlled for potential confounders where possible.

DATA COLLECTION AND MONITORING

Study data will be collected on standardized case report forms. most data will be collected during patient visits to the Community Consortium research nurse. In some instances, it may be necessary to obtain and abstract hospital records, and written from the patient will be obtained. Study data and case report forms will be made available to the FDA.

HUMAN SUBJECTS

This protocol must receive the approval of the participating provider's Institutional Review Board (IRB) prior to implementation. All participants must sign an informed consent form.

LITERATURE CITED

1. Heckler LM and Kotler DP. Malnutrition in patients with AIDS. Nutritional Review 48:393-401, 1990.
2. Kotler DP. Causes and consequences of malnutrition in HIV/AIDS. Nutrition and HIV/AIDS 1:5-8, 1992.
3. Hellerstein MK, Kahn J, Mudie H, et al: Current approach to the treatment of human immunodeficiency virus-associated weight loss: pathophysiological considerations and emerging management strategies. Semin Oncol 17 (suppl 9): 17-33, 1990.
4. Grunfeld C. Metabolic disturbances, anorexia, and wasting in HIV/AIDS. Nutrition and HIV/AIDS 1:9-15, 1992.
5. Lahdevrta J, Mauri CPJ, Teoop A, Relo H. Elevated level of circulation cachectin/TNF in patients with Acquired Immunodeficiency Syndrome. American Journal of Medicine 85:289-291, 1988.
6. Kotler DP, Tierney AR, Want J, and Pierson RN. Magnitude of body-cell-mass depletion and the timing of death from wasting syndrome in AIDS. American Journal of Clinical Nutrition, 50:444-447, 1989.
7. Chlebowski RT, Grosvenor MB, Bernhard NH, et al: Nutritional status, gastrointestinal dysfunction and survival in patients with AIDS, Am J Gastroenterol 84:1288-1293, 1989.
8. Cimoch PJ. Current agents for the management of wasting and malnutrition in HIV/AIDS. Nutrition and HIV/AIDS 1:27-32, 1993.
9. Gorter R. Management of anorexia-cachexia associated with cancer and HIV infection. Oncology 5:13-17, 1991.
10. Gorter R, Seefried M, Volberding P. Dronabinol effects on weight in patients with HIV infection. AIDS 6:127-28, 1992.
11. Struwe M, Kaempfer SH, Geiger CF, et al: Effect of dronabinol on nutritional status in HIV infection. Annals of Pharmacotherapy 27:827-31, 1993.
12. Plasse TF, Gorter RW, Krasnow SH, et al: Recent clinical experience with dronabinol. Pharmacology Biochemistry and Behavior 40:695-700, 1991.
13. Regelson W, Butler JR, Shulz J et al: Delta-9-tetrahydrocannabinol as as effective anti-depressant and appetite stimulation agent in advanced cancer patients, in Braude M, Szara (eds): The Pharmacology of Marijuana, pp 763-776, New York 1976.
14. Olson R, Laubenstein L, Plasse T, Shepard KV. Dronabinol for treatment of anorexia and weight loss in AIDS patients. Presentation at International AIDS Meeting, July 20, 1992, Amsterdam.
15. Vinciguerra V, Moore T, Brennan E: Inhalation marijuana as an antiemetic for cancer chemotherapy, NY State Journal of Medicine 88:525-527, 1988.
16. Greenberg L, Kuchnle J, Mendelson JH, and Bernstein JG, Effects of marijuana use on body weight and caloric intake in humans," Journal of Psychopharmacology (Berlin) 49:79-84, 1976.
17. Foltin RW, Brady JV, and Fischman MW, Behavioral analysis of marijuana's effects on food intake in humans, Pharmacology, Biochemistry and Behavior 25 (1986): 577-582, 1993.
18. Polen M, Sindey S, Tekawa IS et al: Health cares use by frequent marijuana smokers who do not smoke tobacco. The Western Journal of Medicine 158:594-95, 1993.
19. Makyut MO. Health consequences of acute and chronic marijuana use. Prog NeuroPsychopharmacol and Biol Psychiat 9:209-238, 1985.
20. Tashkin DP. Is frequent marijuana smoking harmful to health? The Western Journal of Medicine 158:635-636, 1993.

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