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

NCT03341767 | Terminated Phase 2 DMC

• 2 other identifiers: CFZ-001CC-ID8
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Cryptosporidiosis

Keywords

HIV; Cryptosporidium; Clofazimine

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (4)

• Evaluation of time to negative ELISA signal 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.

  6 days

• Characterization of the stool volume following administration of CFZ relative to placebo.

  6 days

• Characterization of the stool consistency following administration of CFZ relative to placebo.

  6 days

Study Arms (3)

Clofazimine

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Placebo gelatin capsule(s) taken orally every 8 hours for 5 days.

Drug: Placebo

Clofazimine, no diarrhea

EXPERIMENTAL

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

Interventions

Clofazimine DRUG

50 or 100 mg micronized Clofazimine suspended in an oil-wax base in a gelatin capsule

Also known as: Lamprene

Clofazimine; Clofazimine, no diarrhea

Placebo DRUG

Oil-wax in gelatin capsule

Also known as: Placebo (for Clofazimine)

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• Marked prolongation of QT/QTc interval, e.g., confirmed demonstration of QTcF or QTcB interval \>450 ms
• Pathological Q waves (defined as \>40 ms or depth \>0.4 to 0.5mV);
• Electrocardiogram evidence of ventricular pre-excitation
• Electrocardiogram evidence of complete or incomplete left bundle branch block or right bundle branch block
• Electrocardiogram evidence of second or third degree heart block
• Intraventricular conduction delay with QRS duration \>120 ms
• 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

Sponsors & Collaborators

• University of Washington: lead
• Bill and Melinda Gates Foundation: collaborator
• The Emmes Company, LLC: collaborator
• Calibr, a division of Scripps Research: collaborator
• Liverpool School of Tropical Medicine: collaborator
• University of Virginia: collaborator
• Malawi-Liverpool-Wellcome Trust Clinical Research Programme: collaborator

Study Sites (1)

Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW)

Blantyre, Malawi

Location

Related Publications (4)

• 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.

  PMID: 28158186 BACKGROUND

• 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.

  PMID: 34748385 DERIVED

• 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.

  PMID: 32277809 DERIVED

• 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.

  PMID: 30139372 DERIVED

MeSH Terms

Conditions

Cryptosporidiosis

Interventions

Clofazimine

Condition Hierarchy (Ancestors)

Intestinal Diseases, Parasitic; Parasitic Diseases; Infections; Protozoan Infections, Animal; Parasitic Diseases, Animal; Coccidiosis; Protozoan Infections; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Animal Diseases

Intervention Hierarchy (Ancestors)

Phenazines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Wes Van Voorhis, MD, PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, School of Medicine, Allergy & Infectious Diseases

Model Details: Parallel assignment, placebo-controlled with later arm for pharmacokinetics

Study Record Dates

• First Submitted: October 26, 2017
• First Posted: November 14, 2017
• Study Start: December 14, 2017
• Primary Completion: April 1, 2019
• Study Completion: July 5, 2019
• Last Updated: August 13, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

MA (1)