A Phase 2A Evaluation of the Safety, Tolerability, Pharmacokinetics, Efficacy of Clofazimine (CFZ) in Cryptosporidiosis

A Phase 2A, Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety, Tolerability, Pharmacokinetics and Efficacy of Clofazimine (CFZ) in Cryptosporidiosis

This study evaluates the safety, tolerability, pharmacokinetics, and efficacy of treating Cryptosporidiosis in HIV positive patients with Clofazimine. Half of the HIV positive patients with Cryptosporidiosis enrolled will be treated with Clofazimine while the other half will be given placebo. An additional group of HIV positive patients without Cryptosporidium infection or diarrhea will be given Clofazimine to assess the differences in pharmacokinetics between HIV positive patients with and without Cryptosporidiosis and diarrhea.

Study Overview

• Status: Terminated
• Conditions: Cryptosporidiosis
• Intervention / Treatment: Drug: Clofazimine; Drug: Placebo

Detailed Description

Cryptosporidiosium infection and diarrhea is a life-threatening infection in children 6-18 months and in immunocompromised patients. However, Nitazoxanide, the only drug approved for treatment of Cryptosporidiosis, showed little-to-no efficacy in HIV positive patients and low efficacy in malnourished children.

Recently, Love MS et al reported that Clofazimine inhibited proliferation of both Cryptosporidium parvum and C. hominis in vitro and reduced shedding in a mouse model of acute C. parvum infection. Clofazimine has been approved for treatment of leprosy for decades and more recently for the treatment of drug-resistant Mycobacterium tuberculosis. Safety and pharmacokinetics of Clofazimine are well documented for a variety of patient populations, but not for HIV positive patients or patients with diarrhea. Thus, this clinical trial seeks to determine the efficacy of 50 or 100 mg of Clofazimine administered 3 times daily for 5 days on fecal shedding of Cryptosporidium oocysts in HIV positive patients, as well as safety, tolerability, and pharmacokinetics in this patient population.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Malawi
  • Blantyre, Malawi
    • Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Part A:

Inclusion Criteria:

• Male or Female, Aged 18-65 years old, HIV positive, Cryptosporidium positive by qPCR.
• HIV infection and on stable anti-retroviral therapy treatment for at least 2 weeks
• Weight >78 lbs/35.4 kg
• Presents with diarrhea defined as a condition of three or more loose stools per day that has persisted for 3 days or longer
• If female, either not of reproductive potential (post-menopause, or status-post surgical sterilization) or using highly effective contraception (<1% failure, e.g., intrauterine contraceptive device in place or using injectable contraception) or willing to begin highly effective contraception (probably injectable contraception) and continue for the presumed exposure period of Clofazimine (54 days after initiation of treatment)
• Willing and able to provide signed written informed consent or witnessed oral consent in the case of illiteracy, prior to undertaking any trial-related procedures

Exclusion Criteria:

• Any condition for which participation in the study, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
• Fever >38.0˚C at presentation
• Subjects will be screened for evidence of active tuberculosis based on sputum production, fever and chest x-ray. Those with sputum production will be tested by Acid Fast Bacilli stain of sputum smear and/or by GeneXpert testing. Those with positive sputum or chest x-ray suggestive of tuberculosis will be excluded from this study and referred for treatment.
• Is critically ill, or in the judgment of the investigator has a prognosis that could lead to imminent mortality within 60 days or compromise participation in the trial or endanger the subject by entering the trial.
• History of allergy or hypersensitivity to Clofazimine.
• Significant cardiac arrhythmia requiring medication.

• Electrocardiogram exclusions based on the means from triplicate electrocardiograms performed on Day -1:

  1. Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF or QTcB interval >450 ms
  2. Pathological Q waves (defined as >40 ms or depth >0.4 to 0.5mV);
  3. Electrocardiogram evidence of ventricular pre-excitation
  4. Electrocardiogram evidence of complete or incomplete left bundle branch block or right bundle branch block
  5. Electrocardiogram evidence of second or third degree heart block
  6. Intraventricular conduction delay with QRS duration >120 ms
  7. Bradycardia as defined by sinus rate <50 bpm.
• History of additional risk factors for Torsade de Pointes, e.g., heart failure; bradycardia with HR<50 bpm, untreated hypothyroidism, hypokalemia <3.0 mEq/L
• Family history of long QT syndrome
• Use of concomitant medications that markedly prolong the QT/QTc interval or are predicted to have drug-drug interactions with Clofazimine that may lead to toxicity from the partner drug including Amiodarone, Amprenavir, Atazanavir, Bedaquiline, Bepridil, Chloroquine, Chlorpromazine, Cisapride, Clarithromycin, Cyclobenzaprine, Darunavir, Delamanid, Disopyramide Dofetilide, Domperidone, Droperidol, Erythromycin, Fosamprenavir, Halofantrine, Haloperidol, Ibutilide, Indinavir, Levomethadyl, Lopinavir, Mesoridazine, Methadone, Nelfinavir, Pentamidine, Pimozide, Procainamide, Quinidine, Ritonavir, Simiprinivir, Sotalol, Sparfloxacin, Thioridazine, or Tiprinivir
• Pregnant and lactating women (screening pregnancy test for females and pregnancy test at the discharge follow up visit)
• Use of systemic corticosteroids or anti-cryptosporidial treatments within the 28 days preceding Day -1

• Subjects with clinically significant laboratory value abnormalities at screening including but not limited to (note: exclusionary results may not be returned until after enrollment but should be confirmed by the time of the beginning of administration of study drug):

  1. Hemoglobin <5 g/dL
  2. Serum potassium <3.0 mEq/L
  3. Aspartate Aminotransferase or Alanine Aminotransferase ≥3.0 x ULN

Part B:

Same Eligibility Criteria except without diarrhea and is Cryptosporidium negative by qPCR.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Clofazimine; Subjects >/=50 kg: Clofazimine two 50mg gelatin capsules taken orally every 8 hours for 5 days Subjects <50 kg: Clofazimine 50mg gelatin capsule taken orally every 8 hours for 5 days	Drug: Clofazimine; 50 or 100 mg micronized Clofazimine suspended in an oil-wax base in a gelatin capsule; Other Names: Lamprene
PLACEBO_COMPARATOR: Placebo; Placebo gelatin capsule(s) taken orally every 8 hours for 5 days.	Drug: Placebo; Oil-wax in gelatin capsule; Other Names: Placebo (for Clofazimine)
EXPERIMENTAL: Clofazimine, no diarrhea; Subjects >/=50 kg: Clofazimine two 50mg gelatin capsules taken orally every 8 hours for 5 days Subjects <50 kg: Clofazimine 50mg gelatin capsule taken orally every 8 hours for 5 days	Drug: Clofazimine; 50 or 100 mg micronized Clofazimine suspended in an oil-wax base in a gelatin capsule; Other Names: Lamprene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Cryptosporidium fecal shedding following Clofazimine administration	The reduction in the (log) number of Cryptosporidium shed in stools in the first collected stool of the day over a 6-day period and compared to placebo recipients, as measured by quantitative polymerase chain reaction (qPCR) in stool samples and analyzed by a mixed effect ANCOVA analysis in subjects treated according to protocol (ATP).	5 days
Pharmacokinetics (area under curve) of Clofazimine in HIV-infected subjects with Cryptosporidium and diarrhea versus HIV-infected subjects without Cryptosporidium infection or diarrhea	Clofazimine in plasma will be assessed via area under curve.	5 days
Peak plasma concentration of Clofazimine in HIV-infected subjects with Cryptosporidium and diarrhea versus HIV-infected subjects without Cryptosporidium infection or diarrhea	Clofazimine in plasma will be assessed via Cmax and time to reach Cmax (Tmax).	5 days
Pharmacokinetics (Ke) of Clofazimine in HIV-infected subjects with Cryptosporidium and diarrhea versus HIV-infected subjects without Cryptosporidium infection or diarrhea	Clofazimine in plasma will be assessed via Ke determined after the last dose on day 5.	5 days
Stool pharmacokinetics of Clofazimine in HIV-infected subjects with Cryptosporidium and diarrhea versus HIV-infected subjects without Cryptosporidium infection or diarrhea	The total daily amount of CFZ eliminated in stool will be assessed on Study Day 2 (2nd dose day), Study Day 5 (last dose day), and Study Day 6 (concentration of CFZ in stool before discharge).	5 days
Frequency and severity of solicited adverse events (AEs)	Frequency and severity of solicited AEs throughout study product administration	5 days
Frequency, severity, and relationship to study product of unsolicited AEs	Frequency, severity, and relationship to study product of unsolicited AEs throughout the course of the study	55 days
Occurrence of serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs), and adverse events of special interest (AESI).	Occurrence of SAEs, SUSARs, and AESIs throughout the course of the study. AESI include: QT prolongation measured via 12-lead electrocardiogram, liver toxicity, skin discoloration and other skin related AEs/abnormalities (subjects will be evaluated for discoloration of skin of the palms and of the sclera and oral mucous membranes), GI-related AEs.	55 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of time to negative ELISA signal in subjects randomized to Clofazimine versus placebo	Evaluate days required to test negative for Cryptosporidium by ELISA test in subjects randomized to Clofazimine versus placebo.	6 days
Characterization of the reduction in the number of diarrheal episodes following administration of CFZ relative to placebo.	To characterize the reduction in the number of diarrheal episodes following administration of CFZ relative to placebo.	6 days
Characterization of the stool volume following administration of CFZ relative to placebo.	To characterize the stool volume following administration of CFZ relative to placebo.	6 days
Characterization of the stool consistency following administration of CFZ relative to placebo.	To characterize the stool consistency based on a defined diarrheal stool grading scale following administration of CFZ relative to placebo.	6 days

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Bill and Melinda Gates Foundation; University of Virginia; The Emmes Company, LLC; Liverpool School of Tropical Medicine; Malawi-Liverpool-Wellcome Trust Clinical Research Programme; Calibr, a division of Scripps Research
• Investigators: Principal Investigator: Wes Van Voorhis, MD, PhD, University of Washington

Publications and helpful links

General Publications

• Love MS, Beasley FC, Jumani RS, Wright TM, Chatterjee AK, Huston CD, Schultz PG, McNamara CW. A high-throughput phenotypic screen identifies clofazimine as a potential treatment for cryptosporidiosis. PLoS Negl Trop Dis. 2017 Feb 3;11(2):e0005373. doi: 10.1371/journal.pntd.0005373. eCollection 2017 Feb.
• Zhang CX, Love MS, McNamara CW, Chi V, Woods AK, Joseph S, Schaefer DA, Betzer DP, Riggs MW, Iroh Tam PY, Van Voorhis WC, Arnold SLM. Pharmacokinetics and Pharmacodynamics of Clofazimine for Treatment of Cryptosporidiosis. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0156021. doi: 10.1128/AAC.01560-21. Epub 2021 Nov 8.
• Iroh Tam P, Arnold SLM, Barrett LK, Chen CR, Conrad TM, Douglas E, Gordon MA, Hebert D, Henrion M, Hermann D, Hollingsworth B, Houpt E, Jere KC, Lindblad R, Love MS, Makhaza L, McNamara CW, Nedi W, Nyirenda J, Operario DJ, Phulusa J, Quinnan GV, Sawyer LA, Thole H, Toto N, Winter A, Van Voorhis WC. Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial. Clin Infect Dis. 2021 Jul 15;73(2):183-191. doi: 10.1093/cid/ciaa421.
• Nachipo P, Hermann D, Quinnan G, Gordon MA, Van Voorhis WC, Iroh Tam PY. Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial. Trials. 2018 Aug 23;19(1):456. doi: 10.1186/s13063-018-2846-6.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 14, 2017
• Primary Completion (ACTUAL): April 1, 2019
• Study Completion (ACTUAL): July 5, 2019

Study Registration Dates

• First Submitted: October 26, 2017
• First Submitted That Met QC Criteria: November 8, 2017
• First Posted (ACTUAL): November 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 13, 2019
• Last Update Submitted That Met QC Criteria: August 11, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: HIV; Clofazimine; Cryptosporidium
• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Diseases, Parasitic; Parasitic Diseases; Protozoan Infections, Animal; Parasitic Diseases, Animal; Coccidiosis; Protozoan Infections; Cryptosporidiosis; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Bacterial Agents; Leprostatic Agents; Clofazimine
• Other Study ID Numbers: CFZ-001; CC-ID8 (OTHER: The Emmes Corporation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No