Abstract
Natalizumab is a well-established disease-modifying therapy used in active multiple sclerosis (MS). The most serious adverse event is progressive multifocal leukoencephalopathy. For safety reasons, hospital implementation is mandatory. The SARS-CoV-2 pandemic has deeply affected hospital practices leading French authorities to temporarily authorize to administer the treatment at home. The safety of natalizumab home administration should be assessed to allow ongoing home infusion. The aim of the study is to describe the procedure and assess the safety in a home infusion natalizumab model. Patients presenting relapsing-remitting MS treated by natalizumab for over two years, non-exposed to John Cunningham Virus (JCV) and living in the Lille area (France) were included from July 2020 to February 2021 to receive natalizumab infusion at home every four weeks for 12 months. Teleconsultation occurrence, infusion occurrence, infusion cancelling, JCV risk management, annual MRI completion were analyzed. The number of teleconsultations allowing infusion was 365 (37 patients included in the analysis), all home infusions were preceded by a teleconsultation. Nine patients did not complete the one-year home infusion follow-up. Two teleconsultations canceled infusions. Two teleconsultations led to a hospital visit to assess a potential relapse. No severe adverse event was reported. All 28 patients who have completed the follow-up benefited from biannual hospital examination and JCV serologies and annual MRI. Our results suggested that the established home natalizumab procedure was safe using the university hospital home-care department. However, the procedure should be evaluated using home-based services outside the university hospital.
Keywords: Multiple sclerosis, Natalizumab, Home-treatment, Risk, Progressive multifocal leukoencephalopathy
1. Introduction
Natalizumab is a humanized monoclonal antibody binding to α4β1-integrin administered by infusion every four weeks. This disease-modifying therapy (DMT) has proved high efficacy, in relapsing-remitting multiple sclerosis (RRMS), reducing the annualized relapse rate, the incidence of new inflammatory lesions on MRI and worsening of the Kurtzke Expanded Disability Status Scale (EDSS) [1], [2], [3].
The most serious adverse event (AE) is progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the central nervous system. In August 2020, 836 cases of PML had been listed since the commercialization. PML risk is of 4.19/1000 patients per year [4]. This risk is stratified for every patient according to the exposition index to JC virus, treatment duration and prior cytotoxic immunosuppressing treatment [5], [6].
A risk management strategy is established with MRI monitoring, JC virus index monitoring and clinical supervision of the monthly prescription by a neurologist. For all these reasons, natalizumab is only delivered and administered in a healthcare facility. The risk management procedure helped significantly to decrease the incidence of PML case [7], [8].
The SARS-CoV-2 pandemic has deeply modified the hospital care practices in France since spring 2020 including administrative decision of closing beds or restraining the number of patients per room. In other countries, neurologists reported discontinuation of DMT, and many patients confessed deferring one or multiples doses [9]. Interruption of treatment like natalizumab is associated with potential clinical flare-up after eight weeks of discontinuation after [10]. Within this context, French national healthcare authorities called Agence Nationale de Sécurité du Médicament (ANSM) has sent on April 23rd, 2020, a letter authorizing temporarily to administer natalizumab at home in France.
A new model of risk management strategy for home implementation was mandatory. Some authors in Australia and Great-Britain had already reported short positive experience of at-home natalizumab considering mainly patient satisfaction and lack of adverse event related to the infusion [11], [12], [13].
The safety and especially the PML risk management of at-home-natalizumab was not clearly evaluated for this treatment outside the hospital. It was thus decided during the summer 2020 at the Lille University hospital to proceed with home care natalizumab implementation.
The aim of our study is to describe the procedure and assess the safety in a home infusion natalizumab model.
2. Methods
2.1. Study design
We conducted a monocentric retrospective real-life study at the Lille university hospital focused on the observation of a cohort of natalizumab-treated patients receiving natalizumab infusion every four weeks at home for one year. Primary objective was to describe and evaluate the safety of the natalizumab-at-home injection procedure. Secondary objectives were to evaluate the occurrence of MRI completion and JCV index measurement and to evaluate if the natalizumab-at-home injection changed the quality of life of patients.
2.2. Patients
We collected consecutively data from an active file of patients in the Lille university hospital multiple sclerosis (MS) center, initiating home infusion therapy (HIT) from July 2020 to February 2021.
Inclusion criteria were patients over 18 years old, presenting RR-MS followed in the MS center of the University Hospital of Lille, treated by natalizumab for at least 2 years, non-exposed to the JC virus and living in the geographical area covered by the home infusion department of the University Hospital of Lille (20 kilometers around Lille). Exclusion criteria were difficulties to adhere to the treatment and its organization at the hospital during the previous two years and patients with significant cognitive deficiencies.
Protocol information was provided by the investigators for data collection and no opposition from patient was notified. Retrospective data collection was declared to the French data protection authority (CNIL) in January 2022.
2.3. Infusion procedure
A natalizumab infusion procedure was established in accordance with the home hospitalization department (cf. supplementary data 1). After enrolment, the home hospitalization department contacted all patients to explain the functioning modalities of natalizumab home infusions and answer their practical questions.
The home hospitalization department provided to the MS center a schedule every month in agreement with the patients’ availabilities. Infusions were planed every 28 days with a permitted advance or delay of ± 7 days. The patients completing follow-up should have been receiving 13 or 14 infusions every year as expected.
Each teleconsultation was planned and performed before noon the working day preceding the scheduled home infusion. The neurologist and/or the resident assigned to day hospital called the patient and ensured that there was no contraindication such as intercurrent medical event or new neurological symptoms which could challenge the infusion approval. If it was a resident, it was supervised by the neurologist in charge of the day hospital.
Each medical decision to authorize the infusion was documented in the patient medical records. Each teleconsultation canceling the infusion was also documented and communicated online and by phone immediately by the MS center to the home infusion department doctor.
If the infusion was approved, the hospital pharmacy delivered the medication on prescription of the practitioner from the home infusion department. Treatment was then transported at home in a refrigerated box. Before administration, nurses checked the patient vital signs then reconstituted the product. During the one-hour intravenous administration, the nurse left and stayed available by phone. If a problem occurred, they could intervene at home. From January 2022, patients could receive subcutaneous infusion as this galenical form was approved and available. In case of clinical modification, the nurses stopped the infusion and directly called the treating neurologist in the MS center. After administration, vital signs were verified again then the patient received a document with the next infusion date.
2.4. JCV risk management
JCV serology were performed every six months (corresponding to 26 weeks) ± five weeks at the MS center. At the same time, the patients consulted with the neurologist and completed a full clinical assessment including EDSS. A day-care natalizumab infusion was performed on this visit.
Moreover, each patient must have performed an annual MRI ideally in their usual imaging center ± two months during the follow-up (not the same day of natalizumab injection) and the result was documented in the medical file when the neurologist obtained the MRI results.
If neurological status was suspected to have changed, treatment was suspended, and patients must have been visiting the day-care hospital department for medical review as soon as possible.
2.5. Study outcomes
For the primary objective, judgment criteria were the occurrence of teleconsultations and corresponding actions as the occurrence of injection allowed or cancelled, documented in the patients’ medical records. Interval between infusions was calculated in days.
For the secondary objectives, we collected dates of JCV index sampling and results, dates of brain MRI completion and results. The interval between brain MRI was calculated in months. We also collected the reception date of the results in the MS center. All neurological questioning and examination were recorded in the medical file by the neurologist who made the evaluation (dates and scores). Considering tolerance of at-home injection, the procedure and the adverse events were collected by the nurses. Each event must be reported to the treating neurologist and documented in the medical record. Patients completed a quality-of-life questionnaire containing a fatigue impact scale (FIS), an Euroqol five-dimension five level (EQ5D-5L), an Euroqol visual analog scale (EQVAS). The questionnaire was distributed at home by the nurses within the first three months and at the end of follow-up. FIS is made of 40 items about the impact of fatigue on physical, cognitive, psychological concerns ranked from 0 to 4.
EQ5D is made of five dimensions (mobility, autonomy, daily living activities, pain, depression) ranked from level 1 to level 5. EQVAS is a 0-100 scale on which the patient indicates his overall health on the day of questionnaire completion.
2.6. Analysis
Descriptive statistics were calculated for continuous and categorical data. To compare baseline data to follow-up data, we performed matched data set. If the population sample was superior or equal to 30, a Student's t-test was performed. Otherwise, a Shapiro–Wilk test was performed to assess normality. If the data did not follow a normal distribution, a Wilcoxon signed-rank test was performed. Analyses were conducted using the JAMOVI® software [14], [15].
3. Results
3.1. Patients features at baseline
Of the 48 patients eligible in our MS center, 37 patients were included (Fig. 1 ).
Fig. 1.
Flow-chart of multiple sclerosis (MS) patients receiving natalizumab home infusion.
Baseline characteristics are reported in Table 1 . Most participants were female (78.4%). A majority of patients received natalizumab as a second-line drug (62.1%). At baseline, the median duration of the natalizumab treatment was 6 years (range: 2 to 14 years). The median EDSS at inclusion was 2.0 (range: 0 to 4.5). Before inclusion, 36 MRI were compared to the previous MRI, no patient showed signs of activity. Brain MRI control was postponed due to pregnancy for one patient. No patient presented disease activity during the year before baseline.
Table 1.
Baseline demographic characteristics and prior risk management data for 37 patients scheduled to receive natalizumab at home.
| Characteristic | n = 37 |
|---|---|
| Age – year | |
| Mean ± SD | 39.8 ± 11.7 |
| Median (range) | 38 (49) |
| Sex – n (%) | |
| Male | 8 (21.6) |
| Female | 29 (78.4) |
| Disease duration | |
| Mean ± SD | 10.4 ± 5.0 |
| Median (range) | 10 (19) |
| Prior treatment – n (%) | |
| None | 14 (37.8) |
| First-line DMT | 23 (62.1) |
| Natalizumab treatment duration – year | |
| Mean ± SD | 6.7 ± 3.6 |
| Number of relapses in previous two years – n (%) | 0 |
| EDSS at inclusion | |
| Mean ± SD | 1.9 ± 1.1 |
| Median (range) | 2.0 (4.5) |
| Duration between MRI y-1 before inclusion and MRI before inclusion – months | |
| Mean ± SD | 11.7 ± 2.2 |
| Median (range) | 11.0 (11) |
| MRI activity before study – n (%) | 0 |
| Duration between JCV serology tests before inclusion – weeks | |
| Mean ± SD | 26.2 ± 5.0 |
| Median (range) | 25.5 (9) |
DMT: disease-modifying therapy; JCV: John Cunningham virus; SD: standard deviation.
3.2. Teleconsultations and home infusions at end of follow-up
During the study, 367 teleconsultations were made by neurologists. Among them, 365 teleconsultations authorized the infusion. No infusion was performed without the approval of the neurologist making the teleconsultation. A total of 432 infusions (at-home- and in-hospital infusions) were performed including 365 at-home infusions (84.5%). Concerning the administration route at-home, 360 infusions were intravenous and five were subcutaneous. Two teleconsultations did not authorize treatment, one because of a too short interval of 14 days between two infusions due to a scheduling error and one because the patient did not answer the phone despite repeated calls.
Nine patients did not complete the one-year at-home infusion procedure. Four patients returned to the MS center due to JC virus seroconversion. One patient got pregnant. Two patients decided to withdraw from the procedure for personal reasons and one for veinous access difficulties in home hospitalization. We discontinued the treatment for one patient due to the diagnosis of a melanoma.
The patients who completed follow-up, received 11 (39.3%) or 12 at-home infusions (60.7%) associated to two in-hospital infusions as planned.
The mean interval between each infusion was 28.1 ± 2.6 days (SD) (Table 2 ). Almost all interval times (97.5%) were within the time frame of 21 to 35 days between infusions (Fig. 2 ).
Table 2.
Overall results during the one-year follow-up.
| n = 37 | Data before follow-up | P-value | |
|---|---|---|---|
| Teleconsultations – n (%) | |||
| No. of TC authorizing infusion | 365 (99.5) | – | |
| No. of TC rejecting infusion | 2 (0.5) | – | |
| Natalizumab infusion – n (%) | |||
| At-home infusions | 365(84.5) | – | |
| In-hospital infusions | 67 (15.5) | – | |
| Total infusions per patient | |||
| Mean ± SD | 11.6 ± 3.8 | – | |
| Median | 13 | – | |
| Between-infusion interval – days | |||
| Mean ± SD | 28.1 ± 2.6 | – | |
| Median | 28 | – | |
| Range | 18–43 | – | |
| MRI monitoring – n (%)b | |||
| MRI showing activity | 0 (0) | – | |
| Interval between MRI–months | |||
| Mean ± SD | 11.4 ± 2.4 | 11.5 ± 2.0 | 0.69a |
| Median | 12 | 11 | |
| Range | 6–18 | 5–15 | |
| JCV monitoring – n (%)c | |||
| Seroconversions | 4 (11.4) | – | |
| Interval between JCV serology tests during follow-up – weeks | |||
| Mean ± SD | 25.9 ± 1.0 | 25.6 ± 2.7 | 0.65a |
| Median | 26.0 | 26.0 | |
| Range | 24–28 | 20–29 | |
| Neurological status | |||
| Suspicion of flare-up n (%) | 2 (0.05) | – | |
| Confirmed flare-up n (%) | 0 (0) | – |
JCV: John Cunningham virus; SD: standard deviation; TC: teleconsultation.
Student's t-test.
n = 30 patients with available data for matching.
n = 34 patients with available data for matching.
Fig. 2.
Repartition of natalizumab infusion intervals during one year. The 28 days interval represented 69.2% of the total interval amounts. Ten intervals were not in the expected delay and concerned six patients.
3.3. MRI monitoring
During follow-up, 32 MRI were performed, no patient showed new T2 lesions. Five patients performed their annual MRI after their early return to day care hospital. The median delay between the two MRI was 12 months (range: 6–18 months). Two patients who completed the study (6.2%) did not perform their annual MRI during the one-year follow-up. One patient performed the annual MRI at 14 months, but images were seen and documented at the MS center only at 18 months. Two patients benefited from an early MRI surveillance at 6 and 7 months to search for disease activity because the patients reported new neurological symptoms.
There was no significant difference between MRI intervals before (11.5 ± 2.0 months) and during follow-up (11.4 ± 2.4 months) (P = 0.69) (Table 2).
3.4. JCV monitoring
During day hospital visit, 66 JCV serology were performed. All patients who completed the one-year follow-up benefited from two JCV serology.
Eight patients performed their JCV serology after their early withdrawal from the at-home infusion procedure.
Four patients became seropositive during the study. The seroconversion rate was 11.4% (4/35 patients).
No difference was found between JCV serology intervals before enrolment (25.6 ± 2.7 weeks) and during follow-up (25.9 ± 1.0 weeks) (P = 0.65). During follow-up, all intervals were ranged between 20 and 30 weeks with a median time at 25 weeks.
3.5. Neurological status and day-care hospital infusions
Every patient who completed the study had two scheduled in-hospital infusions preceded by a neurological examination.
Two patients needed a supplementary in-hospital visit because of new neurological symptoms. The first one presented exacerbation of gait disorder, clinical examination showed no differences with the latest neurological status. Early cerebral MRI monitoring was performed with no evidence of activity or PML. The patient could have resumed home infusion. The second patient had walking difficulties, comparison of the clinical status by a neurologist showed an aggravation. Anti-natalizumab antibodies measurement was negative. Cerebromedullar MRI was performed and no sign of PML or disease activity were found. The following infusion was made at the hospital to evaluate the evolution. The patient no longer presented functional complaints at this time and could resume home infusion. No patient presented flare-up during follow-up.
3.6. Tolerance
No adverse event due to natalizumab intravenous infusions was reported during follow-up. One patient presented dizziness 30 minutes after the first subcutaneous infusion. One adverse event due to the procedure was described. This patient reported veinous access difficulties at home. No PML case was reported.
3.7. Quality of life
EQ5D were available for 27 (72.9%) patients at start of follow-up (M0) and 18 (66.7%) patients at the end of follow-up (M12). FIS and EQVAS were available for 28 (75.7%) patients at M0 and 20 (71.4%) patients at M12. No difference was found for the QOL and fatigue scores (Table 3 ).
Table 3.
Quality-of-life score at the home infusion start (M0) and after one year of home infusion (M12).
| Score at M0 | Score at M12 | P-value | |
|---|---|---|---|
| EQ5D-5La | |||
| Mean ± SD | 7.50 ± 2.85 | 8.06 ± 2.89 | 0.18 |
| Median | 7.0 | 7.0 | |
| Self-care | |||
| Mean ± SD | 1.13 ± 0.34 | 1.06 ± 0.25 | 1.0 |
| Median | 1.0 | 1.0 | |
| Mobility | |||
| Mean ± SD | 1.56 ± 0.72 | 1.81 ± 0.98 | 0.34 |
| Median | 1.0 | 1.50 | |
| Usual activities | |||
| Mean ± SD | 1.38 ± 0.72 | 1.38 ± 0.72 | 1.0 |
| Median | 1.0 | 1.0 | |
| Pain/discomfort | |||
| Mean ± SD | 1.63 ± 0.88 | 2.0 ± 0.97 | 0.11 |
| Median | 1.0 | 2.0 | |
| Anxiety/depression | |||
| Mean ± SD | 1.81 ± 0.91 | 1.81 ± 0.98 | 1.0 |
| Median | 2.0 | 1.50 | |
| FISb | |||
| Mean ± SD | 38.8 ± 36.4 | 42.8 ± 40.4 | 0.81 |
| Median | 43 | 41 | |
| EQVASb | |||
| Mean ± SD | 78.5 ± 14.7 | 77.4 ± 16.4 | 0.75 |
| Median | 80 | 80 |
EQ5D-5L: Euroqol five-dimension five-level; EQVAS: Euroqol visual analog scale; FIS: fatigue impact scale.
n = 16 patients (number of patients with available data for matching).
n = 19 patients (number of patients with available data for matching).
4. Discussion
Our study showed that the established protocol between MS center and the at-home department allowed that (i) all medical decisions authorizing or cancelling an infusion were followed by the appropriate act; (ii) nearly all (97.5%) intervals between infusions were in the expected delay; (iii) annual MRI monitoring in those JCV-non-exposed patients were performed in the scheduled delay except for two patients; (iv) JCV biannual serologies were performed on time; (v) there were no difference for JCV and MRI delay compared with the day care hospital period preceding the home infusion period; (vi) no severe adverse event was reported.
Previous articles describing the safety of at-home-natalizumab infusion did not give any detail on procedure model allowing or canceling the natalizumab injection for each patient. Considering the importance of PML risk management under natalizumab, all the risks of infusion performed at home and the need for a good patients’ compliance, our inclusion criteria may appear stringent but seemed to us mandatory for a good patient care. They may be one of the reasons for the success of this home infusion project. We decided to include patients after 2 years of natalizumab treatment for immunoallergic risk (the first 6 months), and to initiate the home procedure only in patients who were stabilized and compliant with treatment and PML risk management.
The main limit is the closed-loop design, which ensured to reduce the possible mistakes, but raises the question of reproducibility on a larger scale in collaboration with private out-of-hospital health facilities. The sample of patients is limited but, in the literature, prior studies reporting at-home natalizumab infusion did not exceed 35 patients [13], and we evaluate more than 360 teleconsultation occurrences within one year. Another limit is the retrospective data collection resulting in missing data for the QOL scores, however it was not the primary objective of our study.
The strength of the study was to define practical parameters that can reliably measure the safety procedure: number of teleconsultations expected with the appropriate action arising; measurement of the usual parameters needed to conduct a safe PML risk management. Previous studies in the literature mainly reported the amount of adverse event in limited population size with short follow-up. Obviously, such events remain rare and can stay undetectable. Moreover, this procedure was developed in a MS expert center (CRC SEP), which strengthen its sustainability considering clinical, JCV and MRI assessment and management. In this closed-loop procedure, all three facilities shared the medical files documentations and recordings. There was no missing neurological data because of the exclusive consignation in a centralized software used by all the actors participating in the procedure. It underlines that communication is a key point of the safety procedure.
Our study was the first to describe and to demonstrate measurably the safety of a natalizumab home infusion procedure. Prior studies rather attempted to demonstrate quality of life improvement and treatment tolerance. The implementation of a large majority (84.5%) of the infusions at home allowed patients to stay entirely integrated in their environment and reinforced the “real life” aspect of the study.
Regarding the MRI monitoring under natalizumab the European Medicine Agency recommends at least a yearly MRI. In general, MS patients benefit from annual MRI to monitor the control of the disease activity [16], [17]. With this monitoring in a seronegative population treated by natalizumab, we also try to make up for the false negatives. This strategy was conformed to the practices in 90% of the French MS center [7]. Biannual JCV serologies were performed as recommended [18].
No PML was reported in our study. Since Plavina et al. [6], PML risk stratification, PML cases drastically decreased [7], [8]. Previous at-home natalizumab infusions studies [11], [12], [13] did not report any detail about the risk management procedure.
No AE due to the intravenous infusions were reported, replicating earlier findings [12], [13]. One study [11] reported 70 AE such as fever or infection. The study population had a median EDSS of 6.0 versus 2.0 in our study. No information about the type of infection is available in this article. Nevertheless, natalizumab is not associated with an increased risk of common infections [2]. Higher risk of contracting infection in a more disabled population could explain this difference. In our study, one patient presented a vasovagal reaction during the first subcutaneous infusion. It was difficult to identify if this event was linked to the administration route change or to pain at the injection site. No prior data were found on subcutaneous natalizumab home infusion. The French Health Authority (HAS) reported 4% of pain at the subcutaneous injection site (transparency commission of September 8th, 2021).
Finally, concerning the quality of life, no significant difference was found. However, EQ5D analysis was uninterpretable because of a too small amount of data. Moreover, the FIS completion could be biased because of survey fatigue induced by the amount of questions (40 questions). The use of a modified FIS (21 questions) could have limited this bias. Nine QOL score including a modified FIS were used in a prior study [15]. They did not show any difference between day hospital and home infusion. Beside the small sample size, the evaluation of QOL criteria in an active population may be subject to environmental factors that make the evaluation of fatigue challenging. Considering our patients, as they live very close to Lille, the QoL improvement might not be important enough. We can speculate that the results might be different for patients who are living far from the MS center but are used to come to be treated in Lille.
5. Conclusion and futures perspectives
Our study demonstrates the performance of a natalizumab home infusion procedure considering the JCV risk management in JCV-non-exposed-natalizumab-treated patients. The procedure should be tested in a multicenter study with larger sample size to assure the reproducibility of the model and using a checklist tool for the neurologist and including JCV-seropositive patients with low JCV-index.
Disclosure of interest
JCL, JG, JP, SB declare that they have no competing interest.
JB declares that she has no competing interest. Unrelated to this study, JB received consulting fees from Biogen Idec, Merck, Novartis, Sanofi, Alexion, and had been invited for congresses by Roche.
OO declares that he has no competing interest. Unrelated to this study, OO received consulting fees from Alexion, Roche, Biogen Idec, Novartis, research grant supports from Roche, Novartis, has been invited for congresses by ECTRIMS.
HZ declares that she has no competing interest. Unrelated to this study, HZ received consulting fees from Biogen Idec, Merck, Alexion, Novartis, BMS, Horizon Therapeutics, has been invited for congresses by Roche, Biogen Idec, BMS, received research grant supports from Roche.
Funding of the study
None.
Footnotes
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.neurol.2023.01.727.
Appendix A. Supplementary data
Supplementary data 1. Administration protocol of intravenous targeted therapies by natalizumab TYSABRI® at home, for patients followed in Neurology at the Lille University Hospital.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary data 1. Administration protocol of intravenous targeted therapies by natalizumab TYSABRI® at home, for patients followed in Neurology at the Lille University Hospital.