The BENeFiTS Trial in Beta Thalassemia Intermedia (PB04-001)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT04432623

Recruitment Status : Recruiting

First Posted : June 16, 2020

Last Update Posted : April 15, 2022

See Contacts and Locations

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborator:

National Heart, Lung, and Blood Institute (NHLBI)

Information provided by (Responsible Party):

Phoenicia BioScience

Study Description

Brief Summary:

Beta-thalassemias and hemoglobinopathies are serious inherited blood diseases caused by abnormal or deficiency of beta A chains of hemoglobin, the protein in red blood cells which delivers oxygen throughout the body.The diseases are characterized by hemolytic anemia, organ damage, and early mortality without treatment. Increases in another type of (normal) hemoglobin, fetal globin (HbF), which is normally silenced in infancy, reduces anemia and morbidity. Even incremental augmentation of fetal globin is established to reduce red blood cell pathology, anemia, certain complications, and to improve survival.

This trial will evaluate an oral drug discovered in a high throughput screen, which increases fetal globin protein (HbF and red blood cells expressing HbF)and messenger ribonucleic acid (mRNA) to high levels in anemic nonhuman primates and in transgenic mice. The study drug acts by suppressing 4 repressors of the fetal globin gene promoter in progenitor cells from patients. The drug has been used for 50 years in a combination product for different actions - to enhance half-life and reduce side effects of a different active drug- and is considered safe for long-term use.

This trial will first evaluate 3 dose levels in small cohorts of nontransfused patients with beta thalassemia intermedia. The most active dose will then be evaluated in larger subject groups with beta thalassemia and other hemoglobinopathies, such as sickle cell disease.

Condition or disease	Intervention/treatment	Phase
Beta Thalassemia Intermedia Sickle Cell Disease	Drug: Benserazide Only Product	Phase 1 Phase 2

Detailed Description:

The study will first evaluate 3 doses of the investigational drug which are considered safe with chronic use in a combination therapeutic used widely for a different disease in Europe and Canada. The doses to be studied are human equivalent doses of doses that are active in nonhuman primates in inducing high level fetal globin messenger ribonucleic acid (mRNA), protein, and proportions of red blood cells expressing fetal globin protein (F-cells). Additive effects are observed with hydroxyurea in sickle cell patients' cells in vitro.

The study will first evaluate the study therapeutic in male and female patients who are 18 years and older. After a screening period to obtain baseline medical and laboratory data, the study drug will be taken by mouth once per day, every other day. The first dose will be taken in a clinical unit, and thereafter will be taken at home for 12 weeks. Laboratory tests, physical exams, and tolerability will be assessed 6 times over 4 months, including for one month after completion of dosing.

The cohorts will be enrolled sequentially. Each new cohort will begin after the prior lower dose cohort has received 2 weeks of treatment without serious adverse events related to the study drug. The dose that increases fetal globin assays to the highest degree will be evaluated in a larger group of subjects.Other regimens or test doses may be added as needed to identify an active dose and regimen. The study drug is expected to be safe when added to most other medications used to treat thalassemia.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	36 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Intervention Model Description:	Each higher dose level cohort will be enrolled after 2 weeks of treatment in the lower dose level. Additional doses or regimens may be added. Expansion cohorts at the most active dose will be evaluated.
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1b Sequential Open Label Dose-Ranging Study of Safety, Pharmacokinetics, and Preliminary Activity of Benserazide in Subjects With Beta Thalassemia Intermedia
Actual Study Start Date :	October 5, 2020
Estimated Primary Completion Date :	December 2023
Estimated Study Completion Date :	December 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Sickle cell disease Beta thalassemia

MedlinePlus related topics: Thalassemia

Genetic and Rare Diseases Information Center resources: Sickle Cell Anemia Thalassemia Beta-thalassemia

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Low dose A low dose, by mouth, once per day, on Monday, Wednesday, and Friday for 12 weeks	Drug: Benserazide Only Product Investigational drug
Experimental: Middle dose A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks	Drug: Benserazide Only Product Investigational drug
Experimental: High dose 3 days per week Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks	Drug: Benserazide Only Product Investigational drug
Experimental: High dose 5 days per week The highest dose, by mouth once per day on 5 days per week for 24 weeks	Drug: Benserazide Only Product Investigational drug
Experimental: Sickle Cell Disease Arm The most active dose given once per day on the most active regimen for up 24 weeks	Drug: Benserazide Only Product Investigational drug

Outcome Measures

Primary Outcome Measures :

Safety and Tolerability [ Time Frame: 12 to 24 weeks ]
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Maximum plasma concentration (Cmax) [ Time Frame: 4 weeks ]
drug concentration (ng/ml)
Minimum plasma drug concentration (Cmin) [ Time Frame: 4 weeks ]
Minimum drug plasma concentration, (ng/ml)
Plasma drug concentration over time [ Time Frame: 4 weeks ]
area under the curve

Secondary Outcome Measures :

F-cells [ Time Frame: 12 to 24 weeks ]
% Red blood cells containing HbF
HbF protein per cell [ Time Frame: 12 to 24 weeks ]
Mean fluorescent intensity (MFI)
Fetal hemoglobin (HbF) [ Time Frame: 12 to 24 weeks ]
% and absolute (g/dl)
Hemoglobin [ Time Frame: 16 to 24 weeks ]
gram/dl

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information

Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Beta thalassemia intermedia (BTI) or (NTDT, Non-Transfusion Dependent Thalassemia) with at least one documented beta thalassemia mutation, including HbE beta thalassemia
>18 years of age at time of consent
Average of 2 total hemoglobin (Hgb) levels between 6.0 and 10.0 g/dL in the preceding 6 months
Able and willing to give consent and comply with all study procedures
If female and of childbearing potential, must have a documented negative pregnancy test prior to entry and agree to use one or more locally medically accepted methods of contraception

Exclusion Criteria:

Red blood cell (RBC) transfusion within 2 months prior to administration of study medication
Participating in a chronic transfusion program
Pulmonary hypertension requiring oxygen therapy
Use of erythropoiesis stimulating agents within 90 days of first dose
Transaminases > 3 times upper limit of institution normal (ULN)
Total and direct bilirubin > 3 times institution ULN unless due solely to hemolysis
Known infection with HIV or hepatitis C (untreated)
Fever > 38.5°C in the week prior to first administration of study medication
History of osteoporosis or osteomalacia with a fragility fracture
Received other investigational systemic therapy within 30 days prior to first dose
Narrow angle glaucoma
Currently pregnant or breast feeding a child
Known current drug or alcohol abuse
Taking monoamine oxidase inhibitors
Other co-morbidity that substantially increases subject risk for the study per Investigator discretion

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04432623

Contacts

Layout table for location contacts

Contact: Susan Perrine, MD	617 335-7002	sperrine@bu.edu
Contact: Melissa Askin, RN	410 231-1512	Melissa.Askin@acroclinical.com

Locations

Layout table for location information

United States, California
UCSF Benioff Children's Hospital at Oakland	Recruiting
Oakland, California, United States, 94609
Contact: Sylvia Singer, MD 510-428-3169 Sylvia.Singer@UCSF.edu
Contact: Diego Martinez Mendiola, BA 510- 428-3885 ext 5361 Diego.martinezmendiola@UCSF.edu
Sub-Investigator: Ashtosh Lal, MD
Sub-Investigator: Elliott P Vichinsky, MD
United States, Massachusetts
Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114
Contact: Hanny Al-Samkari, MD 617-643-6214 hal-samkari@mgh.harvard.edu
Susan Perrine	Not yet recruiting
Weston, Massachusetts, United States, 02493
Contact: Susan Perrine, MD 617-335-7002 Sperrine@bu.edu
United States, New York
Weil Cornell Medicine	Recruiting
New York, New York, United States, 10065
Contact: Sujit Sheth, MD 212-746-3400 shethsu@med.cornell.edu
Principal Investigator: Sujit Sheth, MD,MS
Canada, Ontario
University Health Network and Toronto General Hospital	Recruiting
Toronto, Ontario, Canada, M5G2C4
Contact: Kevin Kuo, MD 416 340-4800 ext 6729 Kevin.Kuo@uhn.ca
Contact: RBCD Trial Info Cellphone 437 929-5158 rbcd.clinicaltrials@uhn.ca
Sub-Investigator: Jacob Prendergast, MD

Sponsors and Collaborators

Phoenicia BioScience

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Layout table for investigator information

Study Director:	Susan Perrine, MD	Phoenicia BioScience
Principal Investigator:	Kevin Kuo, MD	University Health Network, Toronto General Hospital
Principal Investigator:	Sylvia Singer, MD	UCSF Benioff Children's Hospital at Oakland
Principal Investigator:	Hanny D Al-Samkari, MD	Massachusetts General Hospital
Principal Investigator:	Sujit Sheth, MD MS	Weill Medical College of Cornell University

More Information

Publications:

Boosalis MS, Sangerman JI, White GL, Wolf RF, Shen L, Dai Y, White E, Makala LH, Li B, Pace BS, Nouraie M, Faller DV, Perrine SP. Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice. PLoS One. 2015 Dec 29;10(12):e0144660. doi: 10.1371/journal.pone.0144660. eCollection 2015.

Dai Y, Sangerman J, Luo HY, Fucharoen S, Chui DH, Faller DV, Perrine SP. Therapeutic fetal-globin inducers reduce transcriptional repression in hemoglobinopathy erythroid progenitors through distinct mechanisms. Blood Cells Mol Dis. 2016 Jan;56(1):62-9. doi: 10.1016/j.bcmd.2015.10.004. Epub 2015 Oct 27.

Dai Y, Sangerman J, Nouraie M, Faller AD, Oneal P, Rock A, Owoyemi O, Niu X, Nekhai S, Maharaj D, Cui S, Taylor R, Steinberg M, Perrine S. Effects of hydroxyurea on F-cells in sickle cell disease and potential impact of a second fetal globin inducer. Am J Hematol. 2017 Jan;92(1):E10-E11. doi: 10.1002/ajh.24590. Epub 2016 Nov 18. No abstract available.

Chen Z, Luo HY, Steinberg MH, Chui DH. BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis. 2009 Mar-Apr;42(2):144-9. doi: 10.1016/j.bcmd.2008.12.003. Epub 2009 Jan 18.

Sedgewick AE, Timofeev N, Sebastiani P, So JCC, Ma ESK, Chan LC, Fucharoen G, Fucharoen S, Barbosa CG, Vardarajan BN, Farrer LA, Baldwin CT, Steinberg MH, Chui DHK. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol Dis. 2008 Nov-Dec;41(3):255-258. doi: 10.1016/j.bcmd.2008.06.007. Epub 2008 Aug 8.

Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet. 2010 Sep;42(9):742-4. doi: 10.1038/ng.637. Epub 2010 Aug 1.

Cao H, Stamatoyannopoulos G, Jung M. Induction of human gamma globin gene expression by histone deacetylase inhibitors. Blood. 2004 Jan 15;103(2):701-9. doi: 10.1182/blood-2003-02-0478. Epub 2003 Aug 14.

Franco RS, Yasin Z, Palascak MB, Ciraolo P, Joiner CH, Rucknagel DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood. 2006 Aug 1;108(3):1073-6. doi: 10.1182/blood-2005-09-008318.

Perrine RP, Brown MJ, Clegg JB, Weatherall DJ, May A. Benign sickle-cell anaemia. Lancet. 1972 Dec 2;2(7788):1163-7. doi: 10.1016/s0140-6736(72)92592-5. No abstract available.

Wang X, Thein SL. Switching from fetal to adult hemoglobin. Nat Genet. 2018 Apr;50(4):478-480. doi: 10.1038/s41588-018-0094-z.

Singer ST, Kuypers FA, Olivieri NF, Weatherall DJ, Mignacca R, Coates TD, Davies S, Sweeters N, Vichinsky EP; E/beta Thalassaemia Study Group. Fetal haemoglobin augmentation in E/beta(0) thalassaemia: clinical and haematological outcome. Br J Haematol. 2005 Nov;131(3):378-88. doi: 10.1111/j.1365-2141.2005.05768.x.

Perrine SP, Mankidy R, Boosalis MS, Bieker JJ, Faller DV. Erythroid Kruppel-like factor (EKLF) is recruited to the gamma-globin gene promoter as a co-activator and is required for gamma-globin gene induction by short-chain fatty acid derivatives. Eur J Haematol. 2009 Jun;82(6):466-76. doi: 10.1111/j.1600-0609.2009.01234.x. Epub 2009 Feb 5.

Tanabe O, McPhee D, Kobayashi S, Shen Y, Brandt W, Jiang X, Campbell AD, Chen YT, Chang Cs, Yamamoto M, Tanimoto K, Engel JD. Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4. EMBO J. 2007 May 2;26(9):2295-306. doi: 10.1038/sj.emboj.7601676. Epub 2007 Apr 12.

Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, Phylactides M, Verkerk AJ, van der Spek PJ, Scerri CA, Cassar W, Galdies R, van Ijcken W, Ozgur Z, Gillemans N, Hou J, Bugeja M, Grosveld FG, von Lindern M, Felice AE, Patrinos GP, Philipsen S. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010 Sep;42(9):801-5. doi: 10.1038/ng.630. Epub 2010 Aug 1.

Atweh GF, Sutton M, Nassif I, Boosalis V, Dover GJ, Wallenstein S, Wright E, McMahon L, Stamatoyannopoulos G, Faller DV, Perrine SP. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood. 1999 Mar 15;93(6):1790-7.

Centis F, Tabellini L, Lucarelli G, Buffi O, Tonucci P, Persini B, Annibali M, Emiliani R, Iliescu A, Rapa S, Rossi R, Ma L, Angelucci E, Schrier SL. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. 2000 Nov 15;96(10):3624-9.

Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood. 1995 Jan 1;85(1):43-9.

Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):226-235. doi: 10.1056/NEJMoa1715971.

Minniti CP. l-Glutamine and the Dawn of Combination Therapy for Sickle Cell Disease. N Engl J Med. 2018 Jul 19;379(3):292-294. doi: 10.1056/NEJMe1800976. No abstract available.

Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007 Jan;21(1):37-47. doi: 10.1016/j.blre.2006.07.001. Epub 2006 Nov 7.

Saraf S, Farooqui M, Infusino G, Oza B, Sidhwani S, Gowhari M, Vara S, Gao W, Krauz L, Lavelle D, DeSimone J, Molokie R, Saunthararajah Y. Standard clinical practice underestimates the role and significance of erythropoietin deficiency in sickle cell disease. Br J Haematol. 2011 May;153(3):386-92. doi: 10.1111/j.1365-2141.2010.08479.x. Epub 2011 Mar 21.

Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr;28(2):233-48. doi: 10.1016/j.hoc.2013.11.009.

Steinberg MH, Rodgers GP. Pharmacologic modulation of fetal hemoglobin. Medicine (Baltimore). 2001 Sep;80(5):328-44. doi: 10.1097/00005792-200109000-00007. No abstract available.

Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010 Jun 3;115(22):4331-6. doi: 10.1182/blood-2010-01-251348. Epub 2010 Mar 16.

Taher AT, Cappellini MD. How I manage medical complications of beta-thalassemia in adults. Blood. 2018 Oct 25;132(17):1781-1791. doi: 10.1182/blood-2018-06-818187. Epub 2018 Sep 11.

Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol. 2007 Aug;138(3):291-304. doi: 10.1111/j.1365-2141.2007.06654.x. Epub 2007 Jun 12.

Sripichai O, Makarasara W, Munkongdee T, Kumkhaek C, Nuchprayoon I, Chuansumrit A, Chuncharunee S, Chantrakoon N, Boonmongkol P, Winichagoon P, Fucharoen S. A scoring system for the classification of beta-thalassemia/Hb E disease severity. Am J Hematol. 2008 Jun;83(6):482-4. doi: 10.1002/ajh.21130.

Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, Kumasaka N, Takahashi A, Svasti S, Munkongdee T, Mahasirimongkol S, Peerapittayamongkol C, Viprakasit V, Kamatani N, Winichagoon P, Kubo M, Nakamura Y, Fucharoen S. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010 Mar;127(3):303-14. doi: 10.1007/s00439-009-0770-2.

Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5. doi: 10.1073/pnas.0711566105. Epub 2008 Feb 1.

Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, Beldjord C, Wajcman H, Fabry ME, Nagel RL. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci U S A. 1985 Apr;82(7):2111-4. doi: 10.1073/pnas.82.7.2111.

Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernandez-Luna JL. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood. 1996 Sep 1;88(5):1576-82.

Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, Wasi P, Ma L, Schrier SL. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood. 2000 Oct 1;96(7):2606-12.

Singer ST, Vichinsky EP, Sweeters N, Rachmilewitz E. Darbepoetin alfa for the treatment of anaemia in alpha- or beta- thalassaemia intermedia syndromes. Br J Haematol. 2011 Jul;154(2):281-4. doi: 10.1111/j.1365-2141.2011.08617.x. Epub 2011 Apr 18. No abstract available.

Layout table for additonal information

Responsible Party:	Phoenicia BioScience
ClinicalTrials.gov Identifier:	NCT04432623
Other Study ID Numbers:	PB04-001 R33HL147845 ( U.S. NIH Grant/Contract )
First Posted:	June 16, 2020 Key Record Dates
Last Update Posted:	April 15, 2022
Last Verified:	April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	Results will be provided in abstracts as the study is being conducted and in a publication after completion and analysis.

Layout table for additional information

Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Phoenicia BioScience:


Non-transfusion dependent beta thalassemia

Additional relevant MeSH terms:

Layout table for MeSH terms

Anemia, Sickle Cell Thalassemia beta-Thalassemia Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn	Benserazide Antiparkinson Agents Anti-Dyskinesia Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Dopamine Agents Neurotransmitter Agents Physiological Effects of Drugs

To Top