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| ID | Type | Description | Link |
|---|---|---|---|
| PC7211 | Other Identifier | Porphyrias Consortium Protocol Number | |
| 1R01FD007287-01 | U.S. FDA Grant/Contract | View source |
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| Name | Class |
|---|---|
| Wake Forest University Health Sciences | OTHER |
| The University of Texas Medical Branch, Galveston | OTHER |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cimetidine | Active Comparator | Cimetidine 800mg orally twice daily |
|
| Placebo | Placebo Comparator | Placebo capsule orally twice daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cimetidine | Drug | Oral Cimetidine 800mg twice daily. |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change in Erythrocyte Total Protoporphyrin Level | Percent change in erythrocyte total protoporphyrin levels after treatment period versus before. | Before and after each 3-month treatment period |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Prodrome | Mean daily self-reported outdoor time, in minutes, before EPP/XLP prodrome onset during the last two months of each treatment period, including days without symptoms. | Last 2 months of each treatment period |
| Change in PROMIS-57 v2 Domain T-scores From Pre-treatment to End of Each 3-month Treatment Period |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Amy K Dickey, MD | Massachusetts General Hospital | Principal Investigator |
| Karl Anderson, MD | University of Texas | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States | ||
| Atrium Health Wake Forest Baptist Medical Center |
Individual participant data that underlie the results reported in the published article, as well as the study protocol and statistical analysis plan, may be shared, after de-identification (text, tables, figures, and appendices), if meeting the time frame and access criteria listed below.
Beginning 9 months and ending 36 months following article publication
With whom: Researchers who provide a methodologically sound proposal that is approved by the study investigators For what type of analysis: To achieve the aims of the approved proposal. By what mechanisms will the data be available: Proposals should be directed to adickey@mgh.harvard.edu . To gain access, data requestors will need to sign a data access agreement.
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A total of 26 patients signed the consent form and were therefore considered enrolled. 25 patients were assigned a randomization group.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo/ Cimetidine | Subjects in this arm were randomized to receive placebo during the first treatment period and cimetidine during the second treatment period. |
| FG001 | Cimetidine/ Placebo | Subjects in this arm were randomized to receive cimetidine during the first treatment period and placebo during the second. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 (3 months) |
| |||||||||||||
| Washout period (3 months) |
| |||||||||||||
| Treatment Period 2 (3 months) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo/ Cimetidine | Subjects in this arm were randomized to receive the Placebo during the first treatment period of the study and Cimetidine during the second treatment period of the study. |
| BG001 | Cimetidine/ Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Age at enrollment |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change in Erythrocyte Total Protoporphyrin Level | Percent change in erythrocyte total protoporphyrin levels after treatment period versus before. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Mean | 95% Confidence Interval | Percent change | Before and after each 3-month treatment period |
|
Throughout the duration of the study; the study duration was approximately 9.5 months per participant
AE analyses included all participants who were randomized and received IP. Twenty-six participants provided informed consent, 25 were randomized, and 3 discontinued during the first month of the first treatment period. One discontinued before randomization. No AEs were reported among the 4 participants who discontinued. AEs during treatment periods were assessed systematically with monthly surveys and phone calls. During the washout period, AEs were recorded when participants reported them.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cimetidine | Oral cimetidine 800mg capsule twice daily | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Urinary tract infection | Renal and urinary disorders | Non-systematic Assessment | Unrelated to study drug |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Amy (Dickey) Yeung, MD | Massachusetts General Hospital | 617-724-4000 | adickey@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 3, 2023 | Mar 6, 2026 | Prot_SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form: Wake Forest Consent | Mar 27, 2025 | Jan 18, 2026 | ICF_000.pdf |
| ICF | No | No | Yes | Informed Consent Form: UTMB Consent Form | Mar 27, 2025 | Jan 18, 2026 | ICF_001.pdf |
| ICF | No | No | Yes | Informed Consent Form: MGH Consent form | Mar 27, 2025 | Jan 18, 2026 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D046351 | Protoporphyria, Erythropoietic |
| C567464 | Protoporphyria, Erythropoietic, X-Linked Dominant |
| D010787 | Photosensitivity Disorders |
| ID | Term |
|---|---|
| D017094 | Porphyrias, Hepatic |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D012873 | Skin Diseases, Genetic |
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| ID | Term |
|---|---|
| D002927 | Cimetidine |
| ID | Term |
|---|---|
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D007093 | Imidazoles |
| D001393 |
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The study design is a multicenter, prospective, randomized, double-blind, placebo-controlled, crossover trial of oral cimetidine 800mg twice daily versus placebo
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randomized, double-blind, placebo-controlled
| Placebo | Drug | Placebo twice daily |
|
PROMIS-57 v2 assesses 7 health domains: Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Domain scores are converted to standardized T-scores with a U.S. general population mean of 50 and standard deviation of 10. Higher scores indicate worse outcomes for Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Interference, and better outcomes for Physical Function and Ability to Participate in Social Roles and Activities. PROMIS-57 v2 was administered immediately before and at the end of each 3-month treatment period. End-of-period PROMIS-57 v2 domain T-scores were analyzed using mixed-effects linear models adjusted for the immediately pre-treatment PROMIS-57 v2 domain T-score for that treatment period, with treatment as a fixed effect and participant as a random effect. Reported values represent least squared means for change in T-score for the cimetidine and placebo treatment periods. |
| Immediately before and at the end of the 3-month cimetidine treatment period, and immediately before and at the end of the 3-month placebo treatment period |
| Change in PROMIS-57 v2 Pain Intensity Scores From Pre-treatment to End of Each 3-month Treatment Period | PROMIS-57 v2 Pain Intensity is a single item scored from 0 to 10, with higher scores indicating worse pain intensity. The instrument-defined possible score range is 0 to 10. This question was administered immediately before and at the end of each 3-month treatment period in this crossover trial. End-of-period PROMIS-57 v2 Pain Intensity scores were analyzed using mixed-effects linear models adjusted for the immediately pre-treatment Pain Intensity score for that treatment period, with treatment as a fixed effect and participant as a random effect. Reported values represent least squared means for change in Pain Intensity scores for the cimetidine and placebo treatment periods. | Immediately before and at the end of the 3-month cimetidine treatment period, and immediately before and at the end of the 3-month placebo treatment period |
| Number of Phototoxic Reactions Per Participant During the Last 2 Months of Each Treatment Period | For each participant, the number of phototoxic reactions during the last 2 months of each 3-month treatment period was recorded. In this crossover trial, the reported outcome compares the number of phototoxic reactions per patient during cimetidine with the number during placebo. | Last 2 months of the 3-month cimetidine treatment period and last 2 months of the 3-month placebo treatment period |
| Blue Light Dose | Average daily outdoor blue light dose before EPP/XLP prodrome onset during the last two months of each treatment period, including days without symptoms. Dose data for the day were excluded if the patient did not wear the dosimeter for the entire day. | Last 2 months of each treatment period |
| Winston-Salem |
| North Carolina |
| 27157 |
| United States |
| University of Texas Medical Branch | Galveston | Texas | 77555 | United States |
| NOT COMPLETED |
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| NOT COMPLETED |
|
Subjects in this arm were randomized to receive the Cimetidine during the first treatment period of the study and Placebo during the second treatment period of the study.
| BG002 | Total | Total of all reporting groups |
| Standard Deviation |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Study Site | Study enrollment site, either Massachusetts General Hospital (MGH) or University of Texas Medical Branch (UTMB) | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Secondary | Time to Prodrome | Mean daily self-reported outdoor time, in minutes, before EPP/XLP prodrome onset during the last two months of each treatment period, including days without symptoms. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Mean | 95% Confidence Interval | Minutes per day | Last 2 months of each treatment period |
|
|
|
|
| Secondary | Change in PROMIS-57 v2 Domain T-scores From Pre-treatment to End of Each 3-month Treatment Period | PROMIS-57 v2 assesses 7 health domains: Physical Function, Anxiety, Depression, Fatigue, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference. Domain scores are converted to standardized T-scores with a U.S. general population mean of 50 and standard deviation of 10. Higher scores indicate worse outcomes for Anxiety, Depression, Fatigue, Sleep Disturbance, and Pain Interference, and better outcomes for Physical Function and Ability to Participate in Social Roles and Activities. PROMIS-57 v2 was administered immediately before and at the end of each 3-month treatment period. End-of-period PROMIS-57 v2 domain T-scores were analyzed using mixed-effects linear models adjusted for the immediately pre-treatment PROMIS-57 v2 domain T-score for that treatment period, with treatment as a fixed effect and participant as a random effect. Reported values represent least squared means for change in T-score for the cimetidine and placebo treatment periods. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Least Squares Mean | 95% Confidence Interval | T-score change | Immediately before and at the end of the 3-month cimetidine treatment period, and immediately before and at the end of the 3-month placebo treatment period |
|
|
|
|
| Secondary | Change in PROMIS-57 v2 Pain Intensity Scores From Pre-treatment to End of Each 3-month Treatment Period | PROMIS-57 v2 Pain Intensity is a single item scored from 0 to 10, with higher scores indicating worse pain intensity. The instrument-defined possible score range is 0 to 10. This question was administered immediately before and at the end of each 3-month treatment period in this crossover trial. End-of-period PROMIS-57 v2 Pain Intensity scores were analyzed using mixed-effects linear models adjusted for the immediately pre-treatment Pain Intensity score for that treatment period, with treatment as a fixed effect and participant as a random effect. Reported values represent least squared means for change in Pain Intensity scores for the cimetidine and placebo treatment periods. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Least Squares Mean | 95% Confidence Interval | Score on a scale change | Immediately before and at the end of the 3-month cimetidine treatment period, and immediately before and at the end of the 3-month placebo treatment period |
|
|
|
|
| Secondary | Number of Phototoxic Reactions Per Participant During the Last 2 Months of Each Treatment Period | For each participant, the number of phototoxic reactions during the last 2 months of each 3-month treatment period was recorded. In this crossover trial, the reported outcome compares the number of phototoxic reactions per patient during cimetidine with the number during placebo. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Geometric Mean | Standard Deviation | phototoxic episodes per patient | Last 2 months of the 3-month cimetidine treatment period and last 2 months of the 3-month placebo treatment period |
|
|
|
|
| Secondary | Blue Light Dose | Average daily outdoor blue light dose before EPP/XLP prodrome onset during the last two months of each treatment period, including days without symptoms. Dose data for the day were excluded if the patient did not wear the dosimeter for the entire day. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Mean | 95% Confidence Interval | mJ/cm^2/day | Last 2 months of each treatment period |
|
|
|
|
| 24 |
| 1 |
| 24 |
| 14 |
| 24 |
| EG001 | Placebo | Oral placebo capsule twice daily | 0 | 23 | 1 | 23 | 9 | 23 |
| EG002 | Washout Period | Three month washout period between Treatment Period 1 and Treatment Period 2 | 0 | 22 | 0 | 22 | 3 | 22 |
|
| Diverticulitis | Gastrointestinal disorders | Non-systematic Assessment | Unrelated to study drug |
|
| Nausea | Nervous system disorders | Non-systematic Assessment |
|
| Heartburn | Gastrointestinal disorders | Non-systematic Assessment |
|
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Transaminitis | Hepatobiliary disorders | Non-systematic Assessment |
|
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| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D011164 | Porphyrias |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| PROMIS-57 Ability to Participate in Social Roles and Activities Score Change |
|
| PROMIS-57 Sleep Disturbance Score Change |
|
| PROMIS-57 Physical Function Score Change |
|
| PROMIS-57 Pain Interference Score Change |
|
| PROMIS-57 Depression Score Change |
|
|
PROMIS-57 v2 Anxiety domain T-scores are standardized to the U.S. general population (mean 50, SD 10). Higher scores indicate worse anxiety. The instrument-defined possible T-score range for this domain is 37.1 to 83.1. |
| Mixed-effects linear model |
Mixed-effects linear model of end-of-period PROMIS-57 v2 domain T-score, adjusted for the immediately pre-treatment domain T-score for that treatment |
| 0.58 |
| Other |
| PROMIS-57 v2 Ability to Participate in Social Roles and Activities domain T-scores are standardized to the U.S. general population (mean 50, SD 10). Higher scores indicate better ability to participate in social roles and activities. The instrument-defined possible T-score range for this domain is 25.9 to 65.4. | Mixed-effects linear model | Mixed-effects linear model of end-of-period PROMIS-57 v2 domain T-score, adjusted for the immediately pre-treatment domain T-score for that treatment | 0.36 | Other |
| PROMIS-57 v2 Sleep Disturbance domain T-scores are standardized to the U.S. general population (mean 50, SD 10). Higher scores indicate worse sleep disturbance. The instrument-defined possible T-score range for this domain is 30.5 to 77.6. | Mixed-effects linear model | Mixed-effects linear model of end-of-period PROMIS-57 v2 domain T-score, adjusted for the immediately pre-treatment domain T-score for that treatment | 0.92 | Other |
| Mixed-effects linear model | Mixed-effects linear model of end-of-period PROMIS-57 v2 domain T-score, adjusted for the immediately pre-treatment domain T-score for that treatment | 0.28 | PROMIS-57 v2 Physical Function domain T-scores are standardized to the U.S. general population (mean 50, SD 10). Higher scores indicate better physical function. The instrument-defined possible T-score range for this domain is 20.9 to 59.7. | Other |
| PROMIS-57 v2 Pain Interference domain T-scores are standardized to the U.S. general population (mean 50, SD 10). Higher scores indicate worse pain interference. The instrument-defined possible T-score range for this domain is 40.7 to 77.0. | Mixed-effects linear model | Mixed-effects linear model of end-of-period PROMIS-57 v2 domain T-score, adjusted for the immediately pre-treatment domain T-score for that treatment | 0.36 | Other |
| PROMIS-57 v2 Depression domain T-scores are standardized to the U.S. general population (mean 50, SD 10). Higher scores indicate worse depression. The instrument-defined possible T-score range for this domain is 38.2 to 81.3. | Mixed-effects linear model | Mixed-effects linear model of end-of-period PROMIS-57 v2 domain T-score, adjusted for the immediately pre-treatment domain T-score for that treatment | 0.17 | Other |