Ileal PouchPhase 1/2PROFNCT05938465
Study of EXE-346 Live Biotherapeutic to Reduce High Bowel Movement Frequency in Subjects With an IPAA (PROF)
A Phase 1/2 study testing EXE-346 in people with Ileal Pouch, run by Exegi Pharma, LLC at 8 sites in United States.
Trial summary
The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346, a live biotherapeutic, which may reduce bowel movement frequency in patients with an ileal pouch-anal anastomosis (IPAA) and lead to a higher quality of life. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Ileal Pouch
- What is being tested?
- EXE-346
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 8 sitesUnited States
- Study dates
- 6 Nov 2023to 31 Jul 2027
- Phase
- Phase 1/2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subject is a male or female and is between the age of 18 to 70 years, inclusive, at screening.
- Subject has had a documented pouchoscopy within 12 months prior to screening.
- Subject or the subject's legally authorized representative is willing and able to provide written informed consent prior to the initiation of any study-related procedures.
- Subject has an average daily bowel movement frequency of at least 10 bowel movements recorded during screening and has correctly completed at least 7 days of eDiary entries during the screening period (Days -13 to 0).
- Subject is a male or female and is aged 18 years or older at screening.
- Subject is willing and able to provide written informed consent prior to the initiation of any study-related procedures.
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- Subject has an average daily bowel movement frequency of at least 10 bowel movements recorded during screening and has correctly completed at least 7 days of eDiary entries during the screening period (Days -21 to 0).
- Inclusion Criteria - Both Phase 1b and Phase 2 Double-Blinded Parts
- Subject has had an IPAA for at least 6 months prior to screening.
- Female subjects of childbearing potential must have a negative serum pregnancy test result at screening and must not be lactating and/or breastfeeding.
- Subjects (female subjects of childbearing potential and male subjects with partners of childbearing potential) must agree to use proper contraceptive methods (see Section 13.2 for contraceptive guidance) to avoid pregnancy during the study. Nonchildbearing potential is defined as at least 6 weeks after a hysterectomy with or without surgical bilateral oophorectomy or postmenopausal (at least 12 months since natural amenorrhea).
- Inclusion Criteria - Optional Open-Label Extension Phase Only
- Subjects must have completed the Phase 2 double-blinded part of the study and are willing to participate in the optional open-label extension phase.
- Note: Subjects who discontinued study treatment in the Phase 2 double-blinded part but who have remained in the study for safety monitoring are eligible for continued safety monitoring in the optional open-label extension phase; however, study treatment will not be re-started in such subjects.
- Subjects must understand the study procedures, the risks involved, and are willing to continue to adhere to the study visit/protocol schedule.
- Exclusion Criteria Subjects meeting any of the criteria specified below for the study phase in which they are enrolling will be excluded from the study.
Who cannot join
- Subject has Crohn's-like disease of the pouch, as indicated by their most recent pouchoscopy during the 12 months prior to screening.
- Subject has a stricture of the IPAA or afferent limb stricture, as indicated by their most recent pouchoscopy during the 12 months prior to screening.
- Subject has taken biologics, azathioprine, or methotrexate within the 12 weeks prior to screening or systemic steroids within 4 weeks of screening.
- Subject has a positive reverse transcriptase-PCR diagnostic test for SARS-CoV-2 within the 14 days prior to screening.
- Subject has uncontrolled hypertension (systolic pressure >160 mm Hg or diastolic pressure >95 mm Hg on at least 2 measures performed at least 10 minutes apart) at screening.
- Subject has Crohn's-like disease of the pouch, as indicated by the pouchoscopy conducted during study screening.
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- Subject has isolated severe cuffitis without pouch inflammation (endoscopic mPDAI score of 2 or lower), as indicated by the pouchoscopy conducted during study screening.
- Subject has a clinically significant stricture of the IPAA or afferent limb stricture which requires surgery or recurrent dilations more than every 3 months, as indicated by the pouchoscopy conducted during study screening. Subjects who have a planned dilation during the active study period are excluded (dilation during the screening pouchoscopy is allowed).
- Subject has taken biologics, azathioprine, methotrexate or small molecules (e.g., JAK inhibitors, S1P receptor modulators) within the 12 weeks prior to screening or systemic steroids within 4 weeks prior to screening.
- Subject has a positive reverse transcriptase-PCR diagnostic test for SARS-CoV-2 within the 7 days prior to screening, per subject self report.
- Subject has an average daily bowel movement frequency of >25 bowel movements recorded during the screening period (Days -21 to 0).
- Subject is taking opioid therapy as a long-term treatment or has taken opioids within 2 weeks prior to screening.
- Subject has taken probiotics within 2 weeks prior to screening.
- Subject has previously received EXE-346 for any duration. Subjects who participated in Phase 1b are excluded from Phase 2.
- Subject has a concurrent, clinically significant, serious, unstable or uncontrolled medical or psychiatric condition that, in the opinion of the investigator, might confound study results, pose additional risk to the subject, or interfere with the subject's ability to participate fully in the study.
- Exclusion Criteria - Both Phase 1b and Phase 2 Double-Blinded Part
- Subject has enterocutaneous or recto- or pouch-vaginal fistula.
- Subject has active Clostridium difficile infection.
- Subject has known or suspected active CMV infection.
- Subject initiated a new treatment with antibiotics or antimotility therapies within the 2 weeks prior to screening or plans to start a new or change doses of a current treatment during the study period (screening visit through the safety follow-up visit [Day 57 in the Phase 1b part or Day 71 in the Phase 2 part]). Subjects taking antibiotics to treat antibiotic-dependent pouchitis or antidiarrheal medication are eligible for the study provided they have been on the therapy at a stable dose for at least 2 weeks prior to screening.
- Subject is taking NSAIDs as a long-term treatment (ie, consistent use for at least 4 days/week each month). Acute use of NSAIDs is allowed.
- Subject has a known history or positive test during screening for HIV, HIV-1, HIV-2, or active HBV or HCV. Active HCV infection is defined as a subject with a positive hepatitis C antibody and detectable hepatitis C viral load RNA.
- Subject has a history of malignancy within the 5 years prior to screening, with the exception of nonmelanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia, or treated in situ grade 1 cervical cancer.
- Subject has estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening.
- Subject has known hypersensitivity to EXE-346 or any product components.
- Female subject is pregnant or lactating and/or breastfeeding.
- Subject has participated in any clinical study of an approved or nonapproved investigational medicinal product within the 30 days prior to screening.
- Subject has any disorder that, in the investigator's opinion, might jeopardize the subject's safety or compliance with the protocol, including but not limited to:
- Decompensated liver disease
- Elevation of AST, ALT, or bilirubin >2 × ULN
- Primary sclerosing cholangitis with elevated transaminases
- Exclusion Criteria - Optional Open-Label Extension Phase Only
- 1. Subjects who have developed any medical or psychologic condition, which was excluded in the Phase 2 double-blinded part of the study or in the opinion of the investigator and/or medical monitor might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.
Trial locations and contacts
8 sites in 1 country. Contact the study team or a site near you to ask about taking part.
8 sites in 1 country
United States8 sites, 8 recruiting
- Recruiting
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599
Mikki Sandridge, 919-843-3873, mikki_sandridge@med.unc.edu
Hannah Gann, 919-843-6961, hannah_gann@med.unc.edu
- Recruiting
Corewell Health
Grand Rapids, Michigan, 49503
Rachel Gross, 616-391-3825, rachel.gross@corewellhealth.org
Jennifer Nguyen, jennifer.nguyen@corewellhealth.org
- Recruiting
Penn State Health (Milton S. Hershey Medical Center)
Hershey, Pennsylvania, 17033
Karen Bright, 717-531-0003 ext. 285155, kbright@pennstatehealth.psu.edu
Ronaldo Paolo Panganiban, MD
- Recruiting
Mayo Clinic - Florida (Inflammatory Bowel Disease Center)
Jacksonville, Florida, 32224
Nic Dybel, 904-953-4324, Dybel.Nicolas@mayo.edu
Mallory Gregory, Gregory.Mallory@mayo.edu
- Recruiting
Cedars-Sinai Medical Center
Los Angeles, California, 90048
Gayane Ovsepyan, 310-289-9224, Gayane.Ovsepyan@cshs.org
Zeyda Cuevas, zeyda.cuevas@cshs.org
- Recruiting
NYU Langone Health
New York, New York, 10016
Alexa Miller, 646-501-8818, alexa.miller@nyulangone.org
Raashi Jain, Raashi.Jain@nyulangone.org
- Recruiting
Mayo Clinic Department of Gastroenterology
Rochester, Minnesota, 55905
Patricia Kammer, 507-538-1827, kammer.patricia@mayo.edu
Christian Cox, Cox.christian@mayo.edu
- Recruiting
Washington University School of Medicine
St Louis, Missouri, 63110
Katherine Huang, 314-273-0301, luluhuang@wustl.edu
Monique Lavalas, lavalas@wustl.edu
About this study
Official title: A Phase 1b/2 Study to Demonstrate the Safety and Efficacy of EXE-346 Live Biotherapeutic to Reduce High Bowel Movement Frequency in Subjects With an Ileal Pouch-Anal Anastomosis (PROF). The "PROF" Study.
The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346, a live biotherapeutic, which may reduce bowel movement frequency in patients with an ileal pouch-anal anastomosis (IPAA) and lead to a higher quality of life.
Read the detailed description
The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346 which may reduce bowel movement frequency in patients with an IPAA and lead to a higher quality of life. EXE-346 is a live biotherapeutic product containing a fixed proportion mixture of 8 individual bacterial strains.
The Phase 1b part of the study is an open label (OL), single-arm study to assess the safety of EXE-346 administered orally for up to 4 weeks.
The Phase 2 part of the study is a randomized, double-blinded study to assess the safety and efficacy of the same dose of EXE-346 administered orally for up to 8 weeks, compared with placebo. Subjects who complete the Phase 2 double-blinded part of the study will be eligible to participate in an optional open label extension phase to receive EXE-346 for up to 8 weeks.
- Conditions
- Ileal Pouch
- Being tested
- EXE-346, Placebo
- Keywords
- Pouchitis, Pouch, Ileal Pouch Anastomosis, IPAA
- Medical subject headings
- Pouchitis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EXE-346Biological
EXE-346 contains a proprietary, fixed-dose, lyophilized blend of 8 strains of gram positive, lactic acid bacteria. EXE-346 excipients are maltose and silicon dioxide.
PlaceboOther
Placebo contains excipients maltose and silicon dioxide.
| Study group | Role | What they receive |
|---|---|---|
| Phase 1b Open Label | Experimental | EXE-346 live biotherapeutic product, 1500x10^9 colony forming units (CFU) twice daily (BID), 4 weeks Receives: Biological: EXE-346 |
| Phase 2: Active Arm | Experimental | EXE-346 live biotherapeutic product, 1500x10^9 CFU BID, 8 weeks Receives: Biological: EXE-346 |
| Phase 2: Placebo Arm | Placebo comparator | Powder containing same inactive ingredients as EXE-346 but none of the active ingredients, BID, 8 weeks Receives: Other: Placebo |
| Phase 2 Open Label Extension (optional) | Experimental | EXE-346 live biotherapeutic product, 1500x10^9 CFU BID, 8 weeks Receives: Biological: EXE-346 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1b: Incidence, Severity, Relatedness, and Frequency of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE)
To assess the safety of EXE-346 using incidence, severity, relationship to study treatment, and frequency of treatment emergent adverse events (TEAE) and serious adverse events (SAE).
Measured: 4 weeks
Phase 1b: Number of Participants with Abnormal Physical Examinations
To assess the safety of EXE-346 using abnormal findings in physical examinations after the start of study treatment that suggest a clinically significant worsening of medical issue.
Measured: 4 weeks
Phase 1b: Number of Participants with Abnormal Vital Signs
To assess the safety of EXE-346 using abnormal findings in vital sign readings after the start of study treatment that suggest a clinically significant worsening of medical issue, including blood pressure.
Measured: 4 weeks
Phase 1b: Number of Participants with Abnormal Safety Labs
To assess the safety of EXE-346 using markedly abnormal findings in safety labs after the start of study treatment that suggest a clinically significant worsening of medical issue.
Measured: 4 weeks
Phase 1b: Study Treatment Discontinuation Due to Treatment Emergent Adverse Events (TEAEs)
To assess the safety of EXE-346 using study treatment discontinuation due to TEAE(s).
Measured: 4 weeks
Phase 2: Incidence, Severity, Relatedness, and Frequency of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE)
To assess the safety of EXE-346 using incidence, severity, relationship to study treatment, and frequency of TEAEs and SAEs.
Measured: 8 weeks
Phase 2: Number of Participants with Abnormal Physical Examinations
To assess the safety of EXE-346 using abnormal findings in physical examinations after the start of study treatment that suggest a clinically significant worsening of medical issue.
Measured: 8 weeks
Phase 2: Number of Participants with Abnormal Vital Signs
To assess the safety of EXE-346 using abnormal findings in vital sign readings after the start of study treatment that suggest a clinically significant worsening of medical issue, including blood pressure.
Measured: 8 weeks
Phase 2: Number of Participants with Abnormal Safety Labs
To assess the safety of EXE-346 using markedly abnormal findings in safety labs after the start of study treatment that suggest a clinically significant worsening of medical issue.
Measured: 8 weeks
Phase 2: Study Treatment Discontinuation Due to Treatment Emergent Adverse Events (TEAEs)
To assess the safety of EXE-346 using study treatment discontinuation due to TEAE(s).
Measured: 8 weeks
Phase 2: Change in Total Daily Bowel Movement Frequency
To assess the efficacy of EXE-346 to reduce the total daily bowel movement frequency using change in average daily bowel movement frequency from baseline to each post-baseline week
Measured: 8 weeks
Phase 2 Open Label: Incidence, Severity, Relatedness, and Frequency of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE)
To assess the safety of EXE-346 using incidence, severity, relationship to study treatment, and frequency of TEAEs and SAEs.
Measured: 8 weeks
Phase 2 Open Label: Number of Participants with Abnormal Physical Examinations
To assess the safety of EXE-346 using abnormal findings in physical examinations after the start of study treatment that suggest a clinically significant worsening of medical issue.
Measured: 8 weeks
Phase 2 Open Label: Number of Participants with Abnormal Vital Signs
To assess the safety of EXE-346 using abnormal findings in vital sign readings after the start of study treatment that suggest a clinically significant worsening of medical issue, including blood pressure.
Measured: 8 weeks
Phase 2 Open Label: Number of Participants with Abnormal Safety Labs
To assess the safety of EXE-346 using markedly abnormal findings in safety labs after the start of study treatment that suggest a clinically significant worsening of medical issue.
Measured: 8 weeks
Phase 2 Open Label: Study Treatment Discontinuation Due to Treatment Emergent Adverse Events (TEAEs)
To assess the safety of EXE-346 using study treatment discontinuation due to TEAE(s).
Measured: 8 weeks
Secondary outcomes (5)
Phase 1b: Bowel Movement Frequency
To assess the effect of EXE-346 on bowel movement frequency using change in average daily bowel movement frequency from baseline to each post-baseline week
Measured: 4 weeks
Phase 1b: Nighttime Awakening Frequency
To assess the effect of EXE-346 on nighttime awakening frequency using change in average nighttime awakenings for bowel movements from baseline to each post-baseline week
Measured: 4 weeks
Phase 1b: Bowel Movement Consistency
To assess the effect of EXE-346 on bowel movement consistency using change in average consistency of daily bowel movements from baseline to each post-baseline week
Measured: 4 weeks
Phase 2: Nighttime Awakening Frequency
To assess the effect of EXE 346 on nighttime awakening frequency using change in average nighttime awakenings for bowel movements from baseline to each post-baseline week
Measured: 8 weeks
Phase 2: Bowel Movement Consistency
To assess the effect of EXE-346 on bowel movement consistency using change in average consistency of daily bowel movements from baseline to each post-baseline week
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Jul 2023
- Study start6 Nov 2023
- Primary completion31 May 2027 (estimated)
- Study completion31 Jul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (39)Papers the sponsor has linked to this study.
- Other trials for Ileal PouchStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Exegi Pharma, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- The Emmes Company, LLC
- Responsible party
- Sponsor
- Investigators
- Julia Collins, MS, Study director, Exegi Pharma, LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05938465
- Sponsor's protocol ID
- 28193
- Acronym
- PROF
- Status last verified
- May 2026
- First submitted
- 30 May 2023
- Last updated
- 28 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Allison J, Herrinton LJ, Liu L, Yu J, Lowder J. Natural history of severe ulcerative colitis in a community-based health plan. Clin Gastroenterol Hepatol. 2008 Sep;6(9):999-1003. doi: 10.1016/j.cgh.2008.05.022.
PubMed 18774533Barnes EL, Herfarth HH, Sandler RS, Chen W, Jaeger E, Nguyen VM, Robb AR, Kappelman MD, Martin CF, Long MD. Pouch-Related Symptoms and Quality of Life in Patients with Ileal Pouch-Anal Anastomosis. Inflamm Bowel Dis. 2017 Jul;23(7):1218-1224. doi: 10.1097/MIB.0000000000001119.
PubMed 28426474Biancone L, Michetti P, Travis S, Escher JC, Moser G, Forbes A, Hoffmann JC, Dignass A, Gionchetti P, Jantschek G, Kiesslich R, Kolacek S, Mitchell R, Panes J, Soderholm J, Vucelic B, Stange E; European Crohn's and Colitis Organisation (ECCO). European evidence-based Consensus on the management of ulcerative colitis: Special situations. J Crohns Colitis. 2008 Mar;2(1):63-92. doi: 10.1016/j.crohns.2007.12.001. Epub 2008 Jan 28. No abstract available.
PubMed 21172196Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri M, De Simone C, Sartor RB. VSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis. Am J Gastroenterol. 2005 Jul;100(7):1539-46. doi: 10.1111/j.1572-0241.2005.41794.x.
PubMed 15984978Bischoff SC, Escher J, Hebuterne X, Klek S, Krznaric Z, Schneider S, Shamir R, Stardelova K, Wierdsma N, Wiskin AE, Forbes A. ESPEN practical guideline: Clinical Nutrition in inflammatory bowel disease. Clin Nutr. 2020 Mar;39(3):632-653. doi: 10.1016/j.clnu.2019.11.002. Epub 2020 Jan 13.
PubMed 32029281Devaraj B, Kaiser AM. Surgical management of ulcerative colitis in the era of biologicals. Inflamm Bowel Dis. 2015 Jan;21(1):208-20. doi: 10.1097/MIB.0000000000000178.
PubMed 25222665Farouk R, Pemberton JH, Wolff BG, Dozois RR, Browning S, Larson D. Functional outcomes after ileal pouch-anal anastomosis for chronic ulcerative colitis. Ann Surg. 2000 Jun;231(6):919-26. doi: 10.1097/00000658-200006000-00017.
PubMed 10816636Gionchetti P, Calafiore A, Riso D, Liguori G, Calabrese C, Vitali G, Laureti S, Poggioli G, Campieri M, Rizzello F. The role of antibiotics and probiotics in pouchitis. Ann Gastroenterol. 2012;25(2):100-105.
PubMed 24714229Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003 May;124(5):1202-9. doi: 10.1016/s0016-5085(03)00171-9.
PubMed 12730861Gionchetti P, Rizzello F, Morselli C, Poggioli G, Tambasco R, Calabrese C, Brigidi P, Vitali B, Straforini G, Campieri M. High-dose probiotics for the treatment of active pouchitis. Dis Colon Rectum. 2007 Dec;50(12):2075-82; discussion 2082-4. doi: 10.1007/s10350-007-9068-4. Epub 2007 Oct 13.
PubMed 17934776Gionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, Poggioli G, Miglioli M, Campieri M. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000 Aug;119(2):305-9. doi: 10.1053/gast.2000.9370.
PubMed 10930365Gower-Rousseau C, Dauchet L, Vernier-Massouille G, Tilloy E, Brazier F, Merle V, Dupas JL, Savoye G, Balde M, Marti R, Lerebours E, Cortot A, Salomez JL, Turck D, Colombel JF. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol. 2009 Aug;104(8):2080-8. doi: 10.1038/ajg.2009.177. Epub 2009 May 12.
PubMed 19436273Hahnloser D, Pemberton JH, Wolff BG, Larson DR, Crownhart BS, Dozois RR. Results at up to 20 years after ileal pouch-anal anastomosis for chronic ulcerative colitis. Br J Surg. 2007 Mar;94(3):333-40. doi: 10.1002/bjs.5464.
PubMed 17225210Herrinton LJ, Liu L, Lewis JD, Griffin PM, Allison J. Incidence and prevalence of inflammatory bowel disease in a Northern California managed care organization, 1996-2002. Am J Gastroenterol. 2008 Aug;103(8):1998-2006. doi: 10.1111/j.1572-0241.2008.01960.x.
PubMed 18796097Hoffmann JC, Zeitz M, Bischoff SC, Brambs HJ, Bruch HP, Buhr HJ, Dignass A, Fischer I, Fleig W, Folsch UR, Herrlinger K, Hohne W, Jantschek G, Kaltz B, Keller KM, Knebel U, Kroesen AJ, Kruis W, Matthes H, Moser G, Mundt S, Pox C, Reinshagen M, Reissmann A, Riemann J, Rogler G, Schmiegel W, Scholmerich J, Schreiber S, Schwandner O, Selbmann HK, Stange EF, Utzig M, Wittekind C. [Diagnosis and therapy of ulcerative colitis: results of an evidence based consensus conference by the German society of Digestive and Metabolic Diseases and the competence network on inflammatory bowel disease]. Z Gastroenterol. 2004 Sep;42(9):979-83. doi: 10.1055/s-2004-813510. No abstract available. German.
PubMed 15455267