Clinical trial NCT05020184: Effect of Oral Cimetidine in the Protoporphyrias
Official title: Effect of Oral Cimetidine in the Protoporphyrias
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Erythropoietic Protoporphyria
X-linked Protoporphyria
Keywords: Erythropoietic Protoporphyria
X-linked Protoporphyria
EPP
Cimetidine
Photosensitivity
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Wake Forest University Health Sciences
name: The University of Texas Medical Branch, Galveston
First posted: 2021-08-25
Enrollment: 26
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The study design is a multicenter, prospective, randomized, double-blind, placebo-controlled, crossover trial of oral cimetidine 800mg twice daily versus placebo
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Erythrocyte total protoporphyrin level
timeFrame: Before and after each 3-month treatment period
Secondary outcomes:
measure: Time to prodrome
timeFrame: Last 2 months of each treatment period
measure: Patient-reported quality of life
timeFrame: Before and after each 3-month treatment period
measure: Phototoxic episodes
timeFrame: Last 2 months of each treatment period
measure: Light dose
timeFrame: Last 2 months of each treatment period
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Winston-Salem
country: United States
facility: Atrium Health Wake Forest Baptist Medical Center
state: North Carolina
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
Study officials:
affiliation: Massachusetts General Hospital
name: Amy K Dickey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas
name: Karl Anderson, MD
role: PRINCIPAL_INVESTIGATOR
References: