PROSpECT-PRIOR-2-CHEMO: PRIOR Dental Intervention Before Chemo to Reduce Chemotherapy Complications

Periodontitis Clinical Trial

Official title:

PROSpECT-PRIOR-2-CHEMO: A Feasibility RCT of Novel Dental Intervention PRIOR[Proactive Intensive Oral Review & Treatment] in Patients Scheduled for Chemotherapy for Myeloma-ASCT & Hematological Cancers to Mitigate Chemotherapy Complications

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06450821
• Other study ID #: 296640
• Status: Not yet recruiting
• Phase: N/A
• Start date: July 2024
• Est. completion date: October 2026

Study information

• Verified date: June 2024
• Source: University of Leeds
• Contact: Sue H Pavitt, PhD
• Phone: +44 7939 014 659
• Email: s.pavitt[@]leeds.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of this feasibility trial is to determine if it is safe and feasible to treat oral health diseases in people with haematological cancers before they start their chemotherapy to reduce complications and disruption to planned chemotherapy dose or schedule.

Description:

PROSpECT PRIOR-2-CHEMO is a feasibility trial which will determine if it is safe and feasible to introduce a new oral health (OH) "PRIOR"(Pro-Active Intensive Oral Review and Treatment prior to chemotherapy) intervention for people with cancer, prior to receiving chemotherapy (CT). PRIOR is a novel interdisciplinary intervention that will be introduced into the current oncology pathway and mirrors the specialist Restorative Dental pathway for patients undergoing treatment for Head and Neck cancers. PRIOR is aimed to be delivered within the relatively short therapeutic window that oncology patients have before commencing their scheduled CT for 1) myeloma-ASCT, or 2) Haematological Allograft SCT . This feasibility phase is valuable to inform a definitive trial. The definitive trial would provide important efficacy and mechanistic understanding of the mitigation of CT adverse events (Aes), specifically life-threatening febrile episodes and painful oral mucositis (OM).

The oral microbiome homeostasis is affected by CT; infection risk is exacerbated by OM, and other dental conditions like periodontal disease (PD) that damage the mucosa, caries, and acute / chronic odontogenic abscesses that collectively predispose to systemic translocation of oral-derived bacteria. With about 35% of the adult population affected by moderate and 10-15% severe periodontitis the importance of improving oral health and reducing bacteria load and portals of entry before CT is logical but seldom undertaken.

Bacteria are responsible for the two most prevalent human oral biofilm-mediated diseases:

dental caries and periodontitis. Periodontitis is a chronic disease caused by inflammatory reactions to gram negative anaerobic bacteria, resulting in irreversible destruction to oral hard and soft tissues. Local inflammation and tissue damage allow oral bacteria to enter the bloodstream. These Immunocompromised patients (such as those receiving CT) are highly susceptible to these invading pathogens which can manifest as life-threatening systemic infections. The risk of developing systemic infections may be associated with the severity of periodontitis (i.e. the total surface area of the ulcerated pocket epithelium) and the composition periodontal pocket microbiota composition. OM is also an inflammatory condition affecting the oral mucosa. OM is a CT-induced complication that not only affects patient's quality of life but also acts as a portal for oral microorganisms and inflammatory products to translocate into the systemic circulation via the ulcerated mucosa. Pre-existing poor oral and periodontal health is a significant risk factors for CT-induced febrile events, creating therapeutic opportunity.

Oral infection, especially periodontitis, may affect the course and pathogenesis of a number of systemic diseases, including cancer, diabetes, and rheumatoid arthritis. The definitive trial will be a hypothesis-driven, mechanistic trial to understand the novel PRIOR intervention vs current NHS standard of care. Specifically, how PRIOR may mitigate Aes across a range of cancer types and CT regimens. The definitive aim is to understand how PRIOR impacts the oral microbial load, the portal entry sites, and the relationship between the oral microbiome, dysbiosis and systemic infection. The investigators will knowledge transfer from mechanistic evaluation of PD in rheumatoid arthritis showing the oral and gut microbiomes were perturbed but partly normalized after treatment. PD shares common mechanisms of action infection/inflammation across several systemic diseases.

Clinical guidelines recommend seeking dental care prior to CT, this may include recommendation to seek dental care with a general dental practitioner (GDP, Primary care), but uptake is low and established care pathways are rare. Consequently, there has been little direct clinical observation by oncology teams of the value of including dental review; In part due to low advocacy by the oncology team, fuelled by little direct clinical observation of the value of including dental review. Patients report significant barriers to achieving dental care prior to CT including access to a GDP, lack of perceived need and logistical challenges.

Patients do not prioritise seeking dental services as they are unaware of the potential importance to their oncology outcomes. The approach is to provide a specialist consultant-led hospital dental team review mirroring the specialist Restorative Dental pathway undertaken by patients having Head and Neck cancer treatment. Specialist dental teams within a secondary care setting may be better placed to deliver inter-disciplinary care than a GDP due to the time limited therapeutic window (therapeutic window defined as the period between diagnosis and deliver of CT). This work is the first to address the clinical need across several cancer patient groups.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: October 2026
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria (mod-high/risk trial participants):

• Adults (= 18years) with scheduled Chemotherapy. Specifically, patients who meet the following diagnosis and treatment window requirements:

• Myeloma- Autologous Stem Cell Transplantation (ASCT) before high-dose myeloablative CT.

• Haematological cancers suitable for Allografts Stem Cell Transplant (SCT) before CT

• Moderate / High Oral Health Risk Assessment - any one of the following:

• Clinical evidence of caries (2+ teeth)

• Clinical evidence on soft and hard tissue examination of infection, sinus, swelling or tenderness

• BPE code 3-4 in any remaining sextant

• BPE code 1-2 with >30% BOP

• The patient is fully informed, has received PIS (patient information sheet) and considered during a 'cooling-off' period, is competent to consent, and is able to comply with minimum attendance requirements

Exclusion Criteria:

• Have a history of head and neck radiotherapy

• Have been treated with Denusomab, Bevacizumab, Sunitinib or Aflibercept within 9 months of the MDT date.

• Insufficient teeth [defined as <2]

• Are incapable of providing informed written consent

• Are unable to comply with minimum attendance requirements

Related Conditions & MeSH terms

• Febrile Neutropenia
• Mucositis
• Myeloma
• Neutropenia
• Oncology
• Oral Mucositis
• Periodontitis
• Stomatitis

Intervention

Procedure:
• PRIOR [Proactive Intensive Oral Review & Treatment]
Intervention Arm: Professional Oral Health Care (POHC) referred to as PRIOR [Proactive Intensive Oral Review & Treatment] prior to chemotherapy.

Locations

Country	Name	City	State
United Kingdom	Dental Translational & Clinical Research Unit (DenTCRU)	Leeds	West Yorkshire

Sponsors (2)

Lead Sponsor	Collaborator
University of Leeds	The Leeds Teaching Hospitals NHS Trust

Country where clinical trial is conducted

United Kingdom, 

References & Publications (12)

Borowski B, Benhamou E, Pico JL, Laplanche A, Margainaud JP, Hayat M. Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: a randomised controlled trial comparing two protocols of dental care. Eur J Cancer B Oral Oncol. 1994;30B(2):93-7. doi: 10.1016/0964-1955(94)90059-0. — View Citation

Brennan MT, Elting LS, Spijkervet FK. Systematic reviews of oral complications from cancer therapies, Oral Care Study Group, MASCC/ISOO: methodology and quality of the literature. Support Care Cancer. 2010 Aug;18(8):979-84. doi: 10.1007/s00520-010-0856-3. Epub 2010 Mar 20. — View Citation

D'Aiuto F, Gkranias N, Bhowruth D, Khan T, Orlandi M, Suvan J, Masi S, Tsakos G, Hurel S, Hingorani AD, Donos N, Deanfield JE; TASTE Group. Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. Lancet Diabetes Endocrinol. 2018 Dec;6(12):954-965. doi: 10.1016/S2213-8587(18)30038-X. Epub 2018 Oct 24. Erratum In: Lancet Diabetes Endocrinol. 2019 Mar;7(3):e3. — View Citation

Jia G, Zhi A, Lai PFH, Wang G, Xia Y, Xiong Z, Zhang H, Che N, Ai L. The oral microbiota - a mechanistic role for systemic diseases. Br Dent J. 2018 Mar 23;224(6):447-455. doi: 10.1038/sj.bdj.2018.217. — View Citation

Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, McGuire DB, Hutchins RD, Peterson DE; Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007 Mar 1;109(5):820-31. doi: 10.1002/cncr.22484. — View Citation

Konig MF, Abusleme L, Reinholdt J, Palmer RJ, Teles RP, Sampson K, Rosen A, Nigrovic PA, Sokolove J, Giles JT, Moutsopoulos NM, Andrade F. Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis. Sci Transl Med. 2016 Dec 14;8(369):369ra176. doi: 10.1126/scitranslmed.aaj1921. — View Citation

Laine PO, Lindqvist JC, Pyrhonen SO, Strand-Pettinen IM, Teerenhovi LM, Meurman JH. Oral infection as a reason for febrile episodes in lymphoma patients receiving cytostatic drugs. Eur J Cancer B Oral Oncol. 1992 Oct;28B(2):103-7. doi: 10.1016/0964-1955(92)90036-z. — View Citation

Momen-Heravi F, Babic A, Tworoger SS, Zhang L, Wu K, Smith-Warner SA, Ogino S, Chan AT, Meyerhardt J, Giovannucci E, Fuchs C, Cho E, Michaud DS, Stampfer MJ, Yu YH, Kim D, Zhang X. Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses' Health Study. Int J Cancer. 2017 Feb 1;140(3):646-652. doi: 10.1002/ijc.30486. Epub 2016 Nov 23. — View Citation

Raber-Durlacher JE, Epstein JB, Raber J, van Dissel JT, van Winkelhoff AJ, Guiot HF, van der Velden U. Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer. 2002 Sep;10(6):466-73. doi: 10.1007/s00520-002-0346-3. Epub 2002 Mar 23. — View Citation

Tsuji K, Shibuya Y, Akashi M, Furudoi S, Yakushijin K, Kawamoto S, Okamura A, Matsuoka H, Komori T. Prospective study of dental intervention for hematopoietic malignancy. J Dent Res. 2015 Feb;94(2):289-96. doi: 10.1177/0022034514561768. Epub 2014 Dec 10. — View Citation

Zecha JAEM, Raber-Durlacher JE, Laheij AMGA, Westermann AM, Epstein JB, de Lange J, Smeele LE. The impact of the oral cavity in febrile neutropenia and infectious complications in patients treated with myelosuppressive chemotherapy. Support Care Cancer. 2019 Oct;27(10):3667-3679. doi: 10.1007/s00520-019-04925-8. Epub 2019 Jun 20. — View Citation

Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants able to attend treatment sessions required for completion of treatment plan, within the defined chemotherapy therapeutic window.	Ability to deliver individualised planned PRIOR intervention within the defined chemotherapy therapeutic window (no less than 7 days before the start of ASCT/allo-SCT) - Number of patients able to attend sessions required by treatment plan	100 days from the date of commencement of chemotherapy (about 4 months from randomisation)
Secondary	Ability to recruit, recruitment rate and acceptability of randomisation	Patients identified by oncology team, suitable for treatment within allotted time frame.; Number of participants identified by oncology team and enrolled onto intervention vs standard of care arm.	Prior to commencement of CT and 100 days after CT
Secondary	Patient compliance with dental referral and treatment plan	Attrition rates. Ability to complete treatment within desired timeframe. Patients may not attend appointments due to various factors e.g. illness, timing etc.; Consent withdrawal from treatment, patients understanding of treatment etc.; Measured by number of patients identified to number of participants who complete treatment	Prior to commencement of CT and 100 days after CT
Secondary	Ability to collect samples (baseline and febrile events) for trial biobank future oral biology testing/mechanistic evaluation	Baseline samples collected by dental team, febrile events collected by oncology team.	Prior to commencement of CT and 100 days after CT
Secondary	Data collection via electronic health records	E.g Oral mucositis and febrile events. Electronic health records accessed by dental team (with patients consent)	Prior to commencement of CT and 100 days after CT
Secondary	Number of participants developing sepsis/bloodstream infection/febrile events	Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Number of participants developing oral mucositis and returning the OMDQ questionnaire	Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Number of participants prescribed an Antibiotic	Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Number of participants with hospital admissions and the length of their hospital stays	Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Number of participants with other (specified) chemotherapy-related complications	Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Number of participants completing Quality of Life Questionnaires	(EORTC QLQ-C30; QLQ-OH15) Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Rate of Mortality	Feasibility of collecting clinical assessments from electronic health records /PROMS [This will also support primary outcome selections and inform power calculations assumptions for a definitive trial]	100 days after CT
Secondary	Process Evaluation	Acceptability of delivery of PRIOR to participants and clinical delivery teams in haematology and dental departments - Focus group/Interviews	post 100 days
Secondary	Inform the design of a definitive RCT. Specifically, whether haematological cancer groups can be combined for efficiency	Ability to perform a power calculation to inform a future trial the ideal number of sites required, to make informed decisions about stop/go progression criteria to monitor the trial's progress effectively.	After completion of study, approximately 18 months