A Phase 2 interventional study of Cimetidine and Placebo in Erythropoietic Protoporphyria and X-linked Protoporphyria, sponsored by Amy K. Dickey, M.D.. Completed at 3 sites in United States. Open to participants aged 15 Years and older. Per ClinicalTrials.gov, last updated 2026-09-04.
Sponsored by Amy K. Dickey, M.D. · Phase 2, Interventional, and Treatment
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.
29 studies on the registry are indexed under Protoporphyria, Erythropoietic; 5 are open to participants now.
This study's enrollment of 26 is below the median of 62 across 20 interventional studies indexed under Protoporphyria, Erythropoietic.
Browse Protoporphyria, Erythropoietic studies →This is the only study on the registry with Amy K. Dickey, M.D. as lead sponsor.
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Exclusion Criteria:
Cimetidine 800mg orally twice daily
Drug: Cimetidine
Placebo capsule orally twice daily
Drug: Placebo
Oral Cimetidine 800mg twice daily.
Also known as: Tagament
Placebo twice daily
Percent Change in Erythrocyte Total Protoporphyrin Level
Percent change in erythrocyte total protoporphyrin levels after treatment period versus before.
Time frame: Before and after each 3-month treatment period
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.
Time frame: 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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Last 2 months of each treatment period
A total of 26 patients signed the consent form and were therefore considered enrolled. 25 patients were assigned a randomization group.
| Milestone | Placebo/ Cimetidine | Cimetidine/ Placebo |
|---|---|---|
| Started | 12 | 13 |
| Completed | 11 | 11 |
| Not completed | 1 | 2 |
| Milestone | Placebo/ Cimetidine | Cimetidine/ Placebo |
|---|---|---|
| Started | 11 | 11 |
| Completed | 11 | 11 |
| Not completed | 0 | 0 |
| Milestone | Placebo/ Cimetidine | Cimetidine/ Placebo |
|---|---|---|
| Started | 11 | 11 |
| Completed | 11 | 11 |
| Not completed | 0 | 0 |
Percent change in erythrocyte total protoporphyrin levels after treatment period versus before.
| Percent change | Placebo | Cimetidine |
|---|---|---|
| Percent Change in Erythrocyte Total Protoporphyrin Level | 5.24 (-6.93 to 17.40) | 10.19 (-4.26 to 24.64) |
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.
| Minutes per day | Placebo | Cimetidine |
|---|---|---|
| Time to Prodrome | 93.89 (72.33 to 115.45) | 107.21 (85.07 to 129.34) |
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.
| T-score change | Placebo | Cimetidine |
|---|---|---|
| PROMIS-57 Fatigue Score Change | -1.46 ± 1.9310 | 0.61 ± 1.9310 |
| PROMIS-57 Anxiety Score Change | -2.61 ± 1.65 | -1.33 ± 1.65 |
| PROMIS-57 Ability to Participate in Social Roles and Activities Score Change | 3.41 ± 2.02 | 5.55 ± 2.02 |
| PROMIS-57 Sleep Disturbance Score Change | 0.06 ± 1.31 | 0.8 ± 1.31 |
| PROMIS-57 Physical Function Score Change | 0.70 ± 1.60 | 2.33 ± 1.60 |
| PROMIS-57 Pain Interference Score Change | 0.64 ± 1.63 | -3.56 ± 1.63 |
| PROMIS-57 Depression Score Change | -0.28 (-2.68 to 2.12) | 1.81 (-0.59 to 4.21) |
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.
| Score on a scale change | Placebo | Cimetidine |
|---|---|---|
| Change in PROMIS-57 v2 Pain Intensity Scores From Pre-treatment to End of Each 3-month Treatment Period | -0.27 (-1.19 to 0.64) | -1.27 (-2.19 to -0.36) |
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.
| phototoxic episodes per patient | Cimetidine | Placebo |
|---|---|---|
| Number of Phototoxic Reactions Per Participant During the Last 2 Months of Each Treatment Period | 2.0 ± 1.6 | 1.8 ± 2.1 |
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.
| mJ/cm^2/day | Placebo | Cimetidine |
|---|---|---|
| Blue Light Dose | 6063.10 (4017.57 to 8108.64) | 5985.22 (3502.59 to 8467.85) |
Collected over Throughout the duration of the study; the study duration was approximately 9.5 months per participant. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cimetidine | 0/24 (0%) | 1/24 (4.2%) | 14/24 (58.3%) |
| Placebo | 0/23 (0%) | 1/23 (4.3%) | 7/23 (30.4%) |
| Washout Period | 0/22 (0%) | 0/22 (0%) | 3/22 (13.6%) |
| Event | Cimetidine | Placebo | Washout Period |
|---|---|---|---|
| Urinary tract infectionRenal and urinary disorders | 0/24 | 1/23 | 0/22 |
| DiverticulitisGastrointestinal disorders | 1/24 | 0/23 | 0/22 |
| Event | Cimetidine | Placebo | Washout Period |
|---|---|---|---|
| Upper respiratory infectionRespiratory, thoracic and mediastinal disorders | 8/24 | 2/23 | 1/22 |
| HeadacheNervous system disorders | 2/24 | 3/23 | 1/22 |
| DiarrheaGastrointestinal disorders | 3/24 | 0/23 | 0/22 |
| TransaminitisHepatobiliary disorders | 0/24 | 2/23 | 0/22 |
| NauseaNervous system disorders | 2/24 | 1/23 | 1/22 |
| HeartburnGastrointestinal disorders | 2/24 | 1/23 | 0/22 |
| Age, Continuous(Years) | Placebo/ Cimetidine | Cimetidine/ Placebo | Total |
|---|---|---|---|
| Mean | 44.8 ± 19.4 | 53.2 ± 13.6 | 49.1 ± 16.9 |
| Sex: Female, Male(Participants) | Placebo/ Cimetidine | Cimetidine/ Placebo | Total |
|---|---|---|---|
| Female | 6 | 7 | 13 |
| Male | 6 | 6 | 12 |
| Race (NIH/OMB)(Participants) | Placebo/ Cimetidine | Cimetidine/ Placebo | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 12 | 13 | 25 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | Placebo/ Cimetidine | Cimetidine/ Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 3 | 3 |
| Not Hispanic or Latino | 12 | 10 | 22 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(Participants) | Placebo/ Cimetidine | Cimetidine/ Placebo | Total |
|---|---|---|---|
| United States | 12 | 13 | 25 |
| Study Site(Participants) | Placebo/ Cimetidine | Cimetidine/ Placebo | Total |
|---|---|---|---|
| MGH | 12 | 12 | 24 |
| UTMB | 0 | 1 | 1 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — 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.
Supporting information: Study protocol, Sap
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