- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05020184
Effect of Oral Cimetidine in the Protoporphyrias
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) result from genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. The objective of this study is to determine the efficacy and safety of oral cimetidine administration for treatment of the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires.
Funding Source- FDA OOPD
Study Overview
Status
Intervention / Treatment
Detailed Description
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are genetic defects of heme biosynthesis that cause life-long, painful cutaneous sensitivity to light. EPP and XLP, collectively called the protoporphyrias, result in the accumulation of the light-sensitive molecule protoporphyrin IX initially in the bone marrow during hemoglobin synthesis and secondarily in erythrocytes, plasma, and the liver. In addition to photosensitivity, protoporphyria can also result in anemia, gallstones, and liver failure. No therapy has been demonstrated to reduce protoporphyrin levels or prevent the potentially life-threatening complications of EPP. Cimetidine has gained attention as a possible treatment for human porphyrias because of a potential off-target effect of inhibition of delta-aminolevulinate synthase (ALAS), the first enzyme of heme biosynthesis. This inhibition was first described in vitro; however, case reports of benefit in EPP have been anecdotal and uncontrolled. Therefore, the objective of this study is to determine the efficacy and safety of oral cimetidine administration in the protoporphyrias. Efficacy will be based on protoporphyrin levels, photosensitivity, and quality of life questionnaires. If the results are positive, this would be the first study providing quality evidence for an agent acting as a disease-modifying therapy for EPP. The study is also attractive because it repurposes an already approved drug with few side effects to treat a rare human disease.
The study design is a prospective, blinded, randomized, 2x2 cross-over design comparing cimetidine to placebo in patients with protoporphyria. Eligible protoporphyria patients will be randomized with equal allocation to one of two treatment sequences that will be administered over two 3-month study periods. Randomization will be stratified by site and permuted block randomization will be used to prevent chronological bias. Patients randomized to sequence 1 will receive placebo during period 1 and cimetidine during period 2. Patients randomized to sequence 2 will receive cimetidine during period 1 and placebo during period 2. Between periods, to eliminate any carry-over effects from the treatment administered in period 1, a wash-out period of 3 months will occur in which all patients receive neither cimetidine nor placebo. Three months was selected for each study period and for the wash-out period because of the rapid decline in protoporphyrin in red cells over the lifespan of the red cell (120 days), as well as to account for the time frame needed to measure light sensitivity in EPP.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Amy K Dickey, MD
- Phone Number: 617-726-1721
- Email: adickey@mgh.harvard.edu
Study Contact Backup
- Name: Paul Y Jiang
- Email: pyjiang@mgh.harvard.edu
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02114
- Recruiting
- Massachusetts General Hospital
-
Principal Investigator:
- Amy K Dickey, MD
-
-
North Carolina
-
Winston-Salem, North Carolina, United States, 27157
- Recruiting
- Atrium Health Wake Forest Baptist Medical Center
-
Principal Investigator:
- Herbert Bonkovsky, MD
-
-
Texas
-
Galveston, Texas, United States, 77555
- Recruiting
- University of Texas Medical Branch
-
Principal Investigator:
- Karl Anderson, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Prior enrollment or co-enrollment in the Longitudinal Study of the Porphyrias (PC Study 7201) with a confirmed diagnosis of EPP or XLP
- Male or female age ≥15 years at screening
- Characteristic history of non-blistering cutaneous photosensitivity
- Willing and capable of giving informed consent and following procedures described in the protocol
Exclusion Criteria:
- Participants not willing to expose themselves to light to the point of prodromal symptoms at least weekly
- History of liver or bone marrow transplant or clinically significant liver dysfunction as determined by the Investigator
- Known or suspected allergy or intolerance to cimetidine
- Use of any other experimental therapy in the past 3 months at screening
- Use of cimetidine within the past 3 months at screening
- Individuals with elevations of porphyrins in plasma or erythrocytes due to other diseases (i.e., secondary porphyrinemia) such as liver and bone marrow diseases
- Patients with any clinically significant comorbid conditions, which in the opinion of the Investigator, precludes participation
- Treatment with any drugs or supplements (Appendix 1) that in the opinion of the Investigator can interfere with subject safety or the objectives of the study
- The participant either does not have a smartphone or is not willing to use his/her smartphone for the study
- Women who are pregnant, breastfeeding, or actively planning to become pregnant
- Individuals with moderate to severe renal insufficiency
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Cimetidine
Cimetidine 800mg orally twice daily
|
Oral Cimetidine 800mg twice daily.
Other Names:
|
Placebo Comparator: Placebo
Placebo capsule orally twice daily
|
Placebo twice daily
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Erythrocyte total protoporphyrin level
Time Frame: Before and after each 3-month treatment period
|
Percent change in erythrocyte total protoporphyrin level post-treatment relative to pre-treatment
|
Before and after each 3-month treatment period
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to prodrome
Time Frame: Last 2 months of each treatment period
|
Time to prodrome measured as prodrome-free outdoor exposure time
|
Last 2 months of each treatment period
|
Patient-reported quality of life
Time Frame: Before and after each 3-month treatment period
|
Patient-reported quality of life as measured by Patient-Reported Outcomes Measurement Information System-57 (PROMIS-57) scale [0-100, where 100 is the best quality of life]
|
Before and after each 3-month treatment period
|
Phototoxic episodes
Time Frame: Last 2 months of each treatment period
|
The number and severity of sunlight-induced pain events (phototoxic episodes)
|
Last 2 months of each treatment period
|
Light dose
Time Frame: Last 2 months of each treatment period
|
Light dose required for time to prodrome
|
Last 2 months of each treatment period
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Amy K Dickey, MD, Massachusetts General Hospital
- Principal Investigator: Karl Anderson, MD, University of Texas
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Metabolic Diseases
- Skin Diseases
- Liver Diseases
- Genetic Diseases, Inborn
- Skin Diseases, Genetic
- Porphyrias, Hepatic
- Porphyrias
- Protoporphyria, Erythropoietic
- Physiological Effects of Drugs
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Gastrointestinal Agents
- Cytochrome P-450 Enzyme Inhibitors
- Anti-Ulcer Agents
- Histamine Antagonists
- Histamine Agents
- Cytochrome P-450 CYP1A2 Inhibitors
- Histamine H2 Antagonists
- Cimetidine
Other Study ID Numbers
- 2021P002095
- PC7211 (Other Identifier: Porphyrias Consortium Protocol Number)
- 1R01FD007287-01 (U.S. FDA Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Erythropoietic Protoporphyria
-
University of UtahNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University... and other collaboratorsTerminatedErythropoietic Protoporphyria (EPP) | X Linked Erythropoietic ProtoporphyriaUnited States
-
University of Alabama at BirminghamPorphyria Rare Disease Clinical Research ConsortiumCompletedErythropoietic Protoporphyria (EPP)United States
-
Mitsubishi Tanabe Pharma America Inc.CompletedErythropoietic Protoporphyria (EPP)United States
-
Icahn School of Medicine at Mount SinaiNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Rare... and other collaboratorsCompletedErythropoietic Protoporphyria | EPP | XLP | X-Linked Protoporphyria | XLPP | X-Linked Dominant Erythropoietic Protoporphyria | XLEPP | XLDPUnited States
-
Brigham and Women's HospitalCompleted
-
Disc Medicine, IncActive, not recruitingErythropoietic ProtoporphyriaUnited States
-
Clinuvel Pharmaceuticals LimitedCompletedErythropoietic ProtoporphyriaNetherlands, Finland, France, Germany, Ireland, United Kingdom
-
Clinuvel Pharmaceuticals LimitedCompletedErythropoietic Protoporphyria
-
Clinuvel Pharmaceuticals LimitedCompletedErythropoietic ProtoporphyriaUnited States
-
Icahn School of Medicine at Mount SinaiNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)CompletedErythropoietic Protoporphyria | EPP | X-linked Protoporphyria | XLPUnited States
Clinical Trials on Placebo
-
SamA Pharmaceutical Co., LtdUnknownAcute Bronchitis | Acute Upper Respiratory Tract InfectionKorea, Republic of
-
National Institute on Drug Abuse (NIDA)CompletedCannabis UseUnited States
-
AstraZenecaParexel; Spandauer Damm 130; 14050; Berlin, GermanyCompletedMale Subjects With Type II Diabetes (T2DM)Germany
-
Heptares Therapeutics LimitedCompletedPharmacokinetics | Safety IssuesUnited Kingdom
-
GlaxoSmithKlineCompletedPulmonary Disease, Chronic ObstructiveUnited Kingdom, Netherlands
-
Shijiazhuang Yiling Pharmaceutical Co. LtdXuanwu Hospital, BeijingCompleted
-
GlaxoSmithKlineCompletedInfections, BacterialUnited States
-
ItalfarmacoCompletedBecker Muscular DystrophyNetherlands, Italy
-
West Penn Allegheny Health SystemCompletedAsthma | Allergic RhinitisUnited States